Improved GIP receptor agonist peptide compounds and uses thereof

Abstract

The present disclosure provides GIP receptor agonist peptide compounds suitable for once per week dosing (QW), said peptide compounds having an activating action on GIP receptors and use of the GIP receptor agonist peptide as a medicament for the treatment and / or prevention of emesis, or a symptom or condition associated with emesis while having an improved profile.

Description

TITLE IMPROVED GIP RECEPTOR AGONIST PEPTIDE COMPOUNDS AND USES THEREOF PRIORITY CLAIM

[0001] This application claims priority to U.S. Provisional Patent Application No.63 / 622,637,filed January 19, 2024, which is incorporated by reference in its entirety. TECHNICAL FIELD

[0002] The present disclosure relates to a novel improved peptide compound having an agonistaction on GIP receptors and use of the peptide compound as a medicament which may be dosed in a once weekly dosing regimen to prevent or treat emesis, and the symptoms of emesis, for example, nausea and / or vomiting. REFERENCE TO THE SEQUENCE LISTING

[0003] This application contains a Sequence Listing which has been submitted electronically inXML format and which is hereby incorporated by reference in its entirety. The XML copy, created on January 17, 2025, is named “223266-538623_Sequence-Listing.xml” and is 66 kilobytes in size. 59057274.1BACKGROUND

[0004] The statements in this section merely provide background information related to thepresent disclosure and may not constitute prior art.

[0005] Both glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropicpolypeptide (GIP) are peptides called incretins. GLP-1 and GIP are secreted from small intestinal L cells and K cells, respectively.

[0006] GLP-1 acts via GLP-1 receptors and is known to have a glucose-dependentinsulinotropic action and a feeding suppressive action. On the other hand, GIP is known to have a glucose-dependent insulinotropic action via the GIP receptors (GIPr), although the effect of GIP alone on feeding (e.g., feeding suppression) is being determined.

[0007] Attempts have been made to search for peptides having GLP-1 receptor / GIP receptorcoagonist or glucagon receptor / GLP-1 receptor / GIP receptor triagonist activity and modifications thereof and develop these peptides as anti-obesity drugs, therapeutic drugs for metabolic diseases (e.g., diabetes, obesity), or therapeutic drugs for other disorders based on the structure of natural glucagon, GIP, or GLP-1. There is a need for novel peptide compounds having a selective activating action on GIP receptors of the present disclosure for the use in treating or preventing emesis and similar symptoms associated with nausea and vomiting. 59057274.1

[0008] Patients who experience nausea and vomiting are often unwilling or unable to take theirmedications regularly; several studies have shown that less frequent dosing results in higher degree of compliance and thus eventually better treatment of the patients. Therefore, there is an unmet need for longer acting preparations of antiemetic medicine. In particular there is a need for longer acting preparations of antiemetic GIP receptor agonist peptides that represent an alternative to twice per day (BID) dosing formulations in order to make a change in dosing regimen, frequency of medication or type of medication, more flexible. Extending the duration of action will also provide a benefit in diseases where the duration of emetic episodes is longer. SUMMARY

[0009] A GIP receptor agonist peptide compound can have a GIP receptor agonism action andcan be useful as a preventive / therapeutic agent for diabetes, obesity, and / or an antiemetic agent to prevent / treat diseases accompanied by vomiting or nausea.

[0010] The present disclosure provides GIPr agonist peptide compounds including a sequencerepresented by Formulae (I), (I-A) and / or (I-B). The GIPr agonist peptide compounds are useful as therapeutic agents for the prevention or treatment of emesis as described herein. Surprisingly, the compounds of Formulae (I), (I-A) and / or (I-B) exhibit excellent GIP receptor activation action, a longer ½ life of elimination and improved solubility (e.g., as compared to that of the native ligand, 59057274.1human native GIP peptide). In some instances, the peptides of Formulae (I), (I-A) and / or (I-B) relative to other known GIPr agonist peptides in the art possess improved properties in one or more of: (1) stability in serum; (2) half-life of elimination; and (3) solubility. In certain embodiments of this disclosure, the peptides of Formulae (I), (I-A) and / or (I-B) relative to other known GIPr agonist peptides that are dosed once per day to treat emesis, or which may be useful as preventative agents of nausea and / or vomiting and other symptoms of emesis, demonstrate an improved profile.

[0011] More specifically, the present disclosure includes the following embodiments:

[0012] In general, a GIP receptor agonist peptide represented by Formula (I):P1-Tyr-Aib-Glu-Gly-Thr-A6-A7-Ser-A9-Tyr-A11-Ile-A13-A14-A15-A16-A17-A18-Gln-A20- A21-Phe-Val-A24-A25-A26-A27-A28-A29-A30-A31-A32-A33-A34-A35-A36-A37-A38-A39- A40-P2(SEQ ID NO: 13), or a pharmaceutically acceptable salt thereof; wherein P1is: H or methyl; P2is: -NH2 or -OH; A6 is: Ala, Leu, Phe, Thr, or Val; A7 is: Ile or Val; A9 is: any amino acid other than Glu or Asp; 59057274.1A11 is: Ser or Phe; A13 is: Aib or Ala; A14 is: Leu, Nle, Met, or Lys(R); A15 is: Asp or Glu; A16 is: Arg or Lys; A17 is: Leu, Glu, Gln, Aib, Ile, or Lys(R); A18 is: Ala, His, or Lys(R); A20 is: Aib, Lys, or Lys(R); A21 is: Glu, Asn, Asp, Lys, Gln, or Lys(R); A24 is: Glu, Asn, Gln, Lys, or Lys(R); A25 is: Ser, Tyr, Trp, or Lys(R); A26 is: Leu or Iva; A27 is: Leu or Ala; A28 is: Ala or Lys; A29 is: Gly, Gln, or Lys(R); A30 is: Glu, Gly, Arg, Lys, or Lys(R); A31 is: Pro or Gly; 59057274.1A32 is: Ser or a deletion; A33 is: Ser or a deletion; A34 is: Gly or a deletion; A35 is: Ala or a deletion; A36 is: Pro or a deletion; A37 is: Pro or a deletion; A38 is: Pro or a deletion; A39 is: Ser or a deletion; and A40 is: Lys, Arg, or a deletion.

[0013] In some embodiments, at least one of A14, A17, A18, A20, A21, A24, A25, A29, orA30 is Lys(R). In some embodiments, at least one of A14, A17, A21, A24, or A30 is Lys(R). In certain embodiments, in the residue Lys(R), the (R) portion represents -L-X, wherein L represents a linker and is selected from the group consisting of OEGgE, 2OEG, 2OEGgE, 2OEGgEgE, 2OEGgEgEgE, 3OEGgE, 3OEGgEgE, G3gEgE, G4gE, G4gEgE, GGGGG, G5gE, G5gEgE, OEGgEgE, and OEGgEgEgE; and X represents C17-C22 monoacid or C17-C22 diacid.

[0014] In some embodiments, A6 is Val. In some embodiments, A6 is Phe. In someembodiments, A6 is not Phe. 59057274.1

[0015] In some embodiments, A7 is Ile, Ala, Leu, Phe, or Val. In some embodiments, A7 is Ileor Val. In some embodiments, A7 is Val.

[0016] In some embodiments, A9 is Ala, Arg, Asn, Cys, Gln, Gly, His, Ile, Leu, Lys, Met, Phe,Pro, Ser, Thr, Trp, Tyr, Val.

[0017] In some embodiments, A9 is Leu.

[0018] In some embodiments, A6 is Val, A7 is Val, and A9 is Leu.

[0019] In some embodiments, A15 is Asp.

[0020] In some embodiments, A30 is Gly, Arg, Lys, or Lys(R).

[0021] In some embodiments, A32-A39 is Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser.

[0022] In some embodiments, the GIP receptor agonist peptide or the pharmaceuticallyacceptable salt thereof, wherein the GIP receptor agonist peptide is of Formula (I-A): P1-Tyr-Aib-Glu-Gly-Thr-Val-A7-Ser-Leu-Tyr-A11-Ile-A13-A14-Asp-A16-A17-A18-Gln-A20- A21-Phe-Val-A24-Trp-A26-A27-A28-A29-A30-A31-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser-A40-P2(SEQ ID NO: 14), or a pharmaceutically acceptable salt thereof; wherein P1is: H or methyl; P2is: -NH2or -OH; 59057274.1A7 is: Ile or Val; A11 is: Ser or Phe; A13 is: Aib or Ala; A14 is: Leu, Nle, Met, or Lys(R); A16 is: Arg or Lys; A17 is: Leu, Glu, Gln, Aib, Ile, or Lys(R); A18 is: Ala, His, or Lys(R); A20 is: Aib, Lys, or Lys(R); A21 is: Glu, Asn, Asp, Lys, Gln, or Lys(R); A24 is: Glu, Asn, Gln, Lys, or Lys(R); A26 is: Leu or Iva; A27 is: Leu or Ala; A28 is: Ala or Lys; A29 is: Gly, Gln, or Lys(R); A30 is: Gly, Arg, Lys, or Lys(R); A31 is: Pro or Gly; A40 is: Lys, Arg, or a deletion; 59057274.1wherein at least one of A14, A17, A18, A20, A21, A24, A25, A29, or A30 is Lys(R); and wherein in the residue Lys(R), the (R) portion represents -L-X, wherein L represents a linker and is selected from the group consisting of 1OEGgE, 2OEG, 2OEGgE, 2OEGgEgE, 2OEGgEgEgE, 3OEGgE, 3OEGgEgE, G3gEgE, G4gE, G4gEgE, GGGGG, G5gE, G5gEgE, OEGgEgE, and OEGgEgEgE; and X represents C17-C22 monoacid or C17-C22 diacid.

[0023] In some embodiments, the GIP receptor agonist peptide or the pharmaceuticallyacceptable salt thereof, is suitable for once-a-week (QW) administration. In some embodiments, the GIP receptor agonist peptide or medicament is administered to the subject once per week, or once per 5-7 days, or four to six times per month.

[0024] In some embodiments, the GIP receptor agonist or the pharmaceutically acceptable saltthereof, wherein X is C17-C22monoacid or diacid, is suitable for once-a-week (QW) administration. In some embodiments, the GIP receptor agonist or the pharmaceutically acceptable salt thereof, wherein X is C17-C24 monoacid or diacid, is suitable for once-a-week (QW) administration. In some embodiments, the GIP receptor agonist peptide or medicament is administered to the subject once per week. In some embodiments, X is a C17 monoacid. In some embodiments, X is a C18 monoacid. In some embodiments, X is a C19monoacid. In some embodiments, X is a C20monoacid. In some embodiments, X is a C21monoacid. In some embodiments, X is a C22monoacid. In some 59057274.1embodiments, X is a C17 diacid (Da). In some embodiments, X is a C18Da. In some embodiments, X is a C19Da. In some embodiments, X is a C20Da. In some embodiments, X is a C21Da. In some embodiments, X is a C22Da. In some embodiments, X is C17monoacid, C18monoacid, C19monoacid, C20monoacid, C21monoacid, C22monoacid, C17diacid (Da), C18diacid, C19 diacid, C20 diacid, C21 diacid or C22 diacid. In some embodiments, X is a C18-C22 diacid. In some embodiments, X is a C18-C20 diacid. In some embodiments, X is a C17 diacid, C18 diacid, C19 diacid, C20 diacid, C21 diacid, or C22 diacid.

[0025] In some embodiments, the GIP receptor agonist peptide is:P1-Tyr-Aib-Glu-Gly-Thr-Val-Val-Ser-Leu-Tyr-A11-Ile-A13-A14-Asp-A16-A17-A18-Gln-A20- A21-Phe-Val-A24-Trp-A26-A27-A28-A29-A30-A31-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser-A40-P2, or a pharmaceutically acceptable salt thereof.

[0026] In some embodiments, A11 is Ser.

[0027] In some embodiments, A13 is Aib.

[0028] In some embodiments, A14 is Leu or Lys(R).

[0029] In some embodiments, A14 is Leu.

[0030] In some embodiments, A14 is Lys(R).

[0031] In some embodiments, A16 is Arg.59057274.1

[0032] In some embodiments, A17 is Glu, Aib, Gln, or Lys(R).

[0033] In some embodiments, A17 is Glu or Aib.

[0034] In some embodiments, A17 is Glu.

[0035] In some embodiments, A17 is Lys(R).

[0036] In some embodiments, A18 is Ala.

[0037] In some embodiments, A20 is Aib.

[0038] In some embodiments, A21 is Glu, Asn, Lys, Gln, or Lys(R).

[0039] In some embodiments, A21 is Lys(R).

[0040] In some embodiments, A24 is Glu, Asn, or Gln.

[0041] In some embodiments, A24 is Asn.

[0042] In some embodiments, A24 is Lys(R).

[0043] In some embodiments, at least one of A14, A17, A21, or A24 is Lys(R). In someembodiments, at least one of A17, A21, or A24 is Lys(R). In some embodiments, at least one of A21 or A24 is Lys(R). In some embodiments, at least one of A21, A24, or A30 is Lys(R). In some embodiments, at least one of A14, A17, A21, A24, or A30 is Lys(R).

[0044] In some embodiments, the residue Lys(R), the (R) portion represents -L-X, and L isselected from the group consisting of 2OEGgE, 2OEGgEgE, and GGGGG. 59057274.1

[0045] In some embodiments, L is 2OEGgE.

[0046] In some embodiments, L is GGGGG.

[0047] In some embodiments, X represents C17-C22 monoacid.

[0048] In some embodiments, X represents C17-C22 diacid.

[0049] In some embodiments, X represents C18 diacid. In some embodiments, X representsC19 diacid. In some embodiments, X represents C20 diacid.

[0050] In some embodiments, A26 is Leu.

[0051] In some embodiments, A28 is Ala.

[0052] In some embodiments, A29 is Gly or Gln.

[0053] In some embodiments, A29 is Gln.

[0054] In some embodiments, A30 is Gly, Arg, or Lys(R).

[0055] In some embodiments, A30 is Gly or Arg.

[0056] In some embodiments, A30 is Gly.

[0057] In some embodiments, A30 is Arg.

[0058] In some embodiments, A30-A31 is Arg-Pro.

[0059] In some embodiments, P1 is H.

[0060] In some embodiments, P1 is methyl.59057274.1

[0061] In some embodiments, P2 is -NH2.

[0062] In some embodiments, A11 is Ser; A13 is Aib or Ala; A14 is Leu or Lys(R); A16 isArg; A17 is Glu, Gln, or Aib; A21 is Glu, Gln, or Lys(R); A24 is Glu, Asn, Gln, or Lys(R); A26is Leu; A29 is Gln; A30 is Gly or Arg; and A40 is a deletion; wherein in the residue Lys(R), the(R) portion represents -L-X, wherein L represents a linker and is selected from the group consisting of 2OEGgE, 2OEG2gE, and GGGGG; and X represents C17-C22 monoacid or C17-C22 diacid.

[0063] In some embodiments, L is 2OEGgE.

[0064] In some embodiments, X represents C17-C22 diacid. In some embodiments, Xrepresents C18-C20diacid.

[0065] In some embodiments, X represents C17 diacid. In some embodiments, X representsC18diacid. In some embodiments, X represents C19diacid. In some embodiments, X represents C20 diacid.

[0066] In some embodiments, A21 is Lys(R); L is selected from the group consisting of2OEGgE and 2OEG2gE; and X represents C17-C22 diacid.

[0067] In some embodiments, A21 is Lys(R); L is 2OEGgE; and X represents C14 diacid.

[0068] In some embodiments, A29 is Gly, Gln, or Lys(R).59057274.1

[0069] In some embodiments, A30 is Gly, Arg, Lys or Lys(R).

[0070] In some embodiments, A11 is: Ser or Phe.

[0071] In some embodiments, A13 is: Aib or Ala.

[0072] In some embodiments, A14 is: Leu, Ile, Nle, Met, or Lys(R). In some embodiments, A14is: Leu, Nle, Met, or Lys(R).

[0073] In some embodiments, A16 is: Arg or Lys.

[0074] In some embodiments, A18 is: Ala, His, or Lys(R).

[0075] In some embodiments, A20 is: Aib, Lys, or Lys(R).

[0076] In some embodiments, A21 is: Glu, Asn, Asp, Lys, Gln, or Lys(R).

[0077] In some embodiments, A26 is: Leu or Iva.

[0078] In some embodiments, A27 is: Leu or Ala.

[0079] In some embodiments, A28 is: Ala or Lys.

[0080] In some embodiments, A29 is: Gly, Gln, or Lys(R).

[0081] In some embodiments, A30 is: Glu, Gly, Arg, Lys, or Lys(R).

[0082] In some embodiments, A32 is: Ser or a deletion.

[0083] In some embodiments, A33 is: Ser or a deletion.

[0084] In some embodiments, A34 is: Gly or a deletion.

[0085] In some embodiments, A35 is: Ala or a deletion.59057274.1

[0086] In some embodiments, A36 is: Pro or a deletion.

[0087] In some embodiments, A37 is: Pro or a deletion.

[0088] In some embodiments, A38 is: Pro or a deletion.

[0089] In some embodiments, A39 is: Ser or a deletion.

[0090] In some embodiments, A40 is: Lys, Arg, or a deletion.

[0091] In some embodiments, the GIP receptor agonist peptide has at least three unnaturalamino acids.

[0092] In some embodiments, A40 is a deletion.

[0093] In some embodiments, the GIP receptor agonist peptide is of Formula (I-B):P1-Tyr-Aib-Glu-Gly-Thr-Val-Val-Ser-Leu-Tyr-Ser-Ile-Aib-Leu-Asp-A16-Glu-A18-Gln-A20- A21-Phe-Val-Asn-Trp-A26-A27-A28-A29-A30-Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser-A40-P2(SEQ ID NO: 15); wherein A21 is Lys(R); wherein in the residue Lys(R), the (R) portion represents -L-X, wherein L represents a linker and is selected from the group consisting of 2OEGgE, 2OEGgEgE, and GGGGG (G5); and X represents C17-C22 monoacid or C17-C22 diacid; and A40 is a deletion.

[0094] In some embodiments, the GIP receptor agonist peptide has at least three unnaturalamino acids. 59057274.1

[0095] In some embodiments, the GIP receptor agonist peptide has three unnatural aminoacids.

[0096] In some embodiments, the three unnatural amino acids are each Aib.

[0097] In some embodiments, the GIP receptor agonist peptide has at least 30 amino acid residues.In some embodiments, the GIP receptor agonist peptide has at least 30 amino acid residues or at least 32 amino acid residues, e.g., 30-40 amino acid residues. In some embodiments, the GIP receptor agonist peptide has at least 32 amino acid residues.

[0098] In some embodiments, the GIP receptor agonist peptide has 30-40 amino acid residues.In some embodiments, the GIP receptor agonist peptide has 32-40 amino acid residues.

[0099] In some embodiments, the GIP receptor agonist peptide has 39 amino acid residues.

[0100] In some embodiments, the GIP receptor agonist peptide is:H-Tyr-Aib-Glu-Gly-Thr-Val-Val-Ser-Leu-Tyr-Ser-Ile-Aib-Lys(R)-Asp-Arg-Glu-Ala-Gln-Aib- Glu-Phe-Val-Asn-Trp-Leu- Leu-Ala-Gln-Arg-Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser-NH2; and Lys(R) is 2OEGgE-C15 diacid.

[0101] In some embodiments, the GIP receptor agonist peptide is:H-Tyr-Aib-Glu-Gly-Thr-Val-Val-Ser-Leu-Tyr-Ser-Ile-Aib-Leu-Asp-Arg-Glu-Ala-Gln-Aib- Lys(R)-Phe-Val-Asn-Trp-Leu-Leu-Ala-Gln-Arg-Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser-NH2; and 59057274.1Lys(R) is 2OEGgE-C14 diacid.

[0102] In some embodiments, the GIP receptor agonist peptide is:H-Tyr-Aib-Glu-Gly-Thr-Val-Val-Ser-Leu-Tyr-Ser-Ile-Aib-Leu-Asp-Arg-Glu-Ala-Gln-Aib- Lys(R)-Phe-Val-Asn-Trp-Leu-Leu-Ala-Gln-Arg-Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser-NH2; and Lys(R) is 2OEGgE-C17 monoacid.

[0103] In some embodiments, the GIP receptor agonist peptide is:H-Tyr-Aib-Glu-Gly-Thr-Val-Val-Ser-Leu-Tyr-Ser-Ile-Aib-Leu-Asp-Arg-Glu-Ala-Gln-Aib- Lys(R)-Phe-Val-Glu-Trp-Leu-Leu-Ala-Gln-Arg-Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser-NH2; and Lys(R) is 2OEGgE-C18diacid. In some embodiments, X represents C19diacid. In some embodiments, X represents C20diacid.

[0104] In some embodiments, the GIP receptor agonist peptide is more selective for (e.g., moreselective for binding) GIPR than other G protein-coupled receptors (GPCR’s) (e.g., GLP1). In some embodiments, the GIP receptor agonist peptide has a selectivity ratio, expressed as a ratio of (GLP1R EC50 / GIPR EC50) of greater than 10, or greater than 100, or greater than 1,000, greater than 10,000, or greater than 100,000.

[0105] In some embodiments, the GIP receptor agonist peptide has an IV half life ofelimination ranging between about 4 – 14 hours (e.g., about 4-6 hours, about 6-8 hours, about 6-8 59057274.1hours, about 8-10 hours, about 10-12 hours, about 12-14 hours), in a mammal (e.g., human).

[0106] In some embodiments, the GIP receptor agonist peptide has a solubility of 15 mg / mLor greater at pH 7.4.

[0107] In some embodiments, the GIP receptor agonist peptide has a solubility of 30 mg / mLor greater at pH 7.4.

[0108] In some embodiments, a medicament can include the GIP receptor agonist peptidesdiscussed herein, or a pharmaceutically acceptable salt thereof.

[0109] In some embodiments, the medicament is an activator of a GIP receptor.

[0110] In some embodiments, the medicament is a suppressant for vomiting or nausea.

[0111] In some embodiments, a pharmaceutical composition can include the GIP receptoragonist peptide described herein, or a pharmaceutically acceptable salt thereof.

[0112] In some embodiments, the GIP receptor agonist peptide, or a pharmaceuticallyacceptable salt thereof, or the medicament, or the pharmaceutical composition discussed herein, is administered to treat emesis as a monotherapy.

[0113] In some embodiments, the GIP receptor agonist peptide, or a pharmaceuticallyacceptable salt thereof, or the medicament, or the pharmaceutical composition, is administered to a subject Q1D, or once per 24 hours to treat or prevent emesis, including vomiting and / or nausea. 59057274.1

[0114] In some embodiments, the GIP receptor agonist peptide, or a pharmaceuticallyacceptable salt thereof, or the medicament, or the pharmaceutical composition is used in suppressing vomiting or nausea.

[0115] In some embodiments, the use of the GIP receptor agonist peptide, or apharmaceutically acceptable salt thereof, or the medicament, or the pharmaceutical composition, is used for the manufacture of a suppressant for vomiting or nausea.

[0116] In certain embodiments, a method of activating of a GIP receptor, can includeadministering a GIP receptor agonist peptide discussed herein, e.g., to a subject in need thereof (e.g., a human).

[0117] In some embodiments, a method of preventing or treating emesis in a subject, caninclude administering to the subject an effective amount of the GIP receptor agonist peptide discussed herein, or a pharmaceutically acceptable salt thereof, or the medicament, or the pharmaceutical composition discussed herein.

[0118] In some embodiments, the emesis is nausea and / or vomiting.

[0119] In some embodiments, the method can include activating of a GIP receptor.

[0120] In some embodiments, the activating of a GIP receptor can include an improved and / ordifferent pharmacological profile. 59057274.1

[0121] In some embodiments, the GIP receptor agonist peptide discussed herein, or apharmaceutically acceptable salt thereof, or the medicament, or the pharmaceutical composition, or the method, where the emesis, vomiting, or the nausea is caused by one or more conditions or causes selected from the following group consisting of options (1) to (10): (1) Diseases accompanied by vomiting or nausea such as gastroparesis, gastrointestinal hypomotility, peritonitis, abdominal tumor, constipation, gastrointestinal obstruction, chronic intestinal pseudo-obstruction, functional dyspepsia, cyclic vomiting syndrome, chronic unexplained nausea and vomiting, acute pancreatitis, chronic pancreatitis, hepatitis, hyperkalemia, cerebral edema, intracranial lesion, metabolic disorder, gastritis caused by an infection, postoperative disease, myocardial infarction, migraine, intracranial hypertension, and intracranial hypotension (e.g., altitude sickness); (2) Vomiting and / or nausea induced by chemotherapeutic drugs such as (i) alkylating agents (e.g., cyclophosphamide, carmustine, lomustine, chlorambucil, streptozocin, dacarbazine, ifosfamide, temozolomide, busulfan, bendamustine, and melphalan), cytotoxic antibiotics (e.g., dactinomycin, doxorubicin, mitomycin-C, bleomycin, epirubicin, actinomycin D, amrubicin, idarubicin, daunorubicin, and pirarubicin), antimetabolic agents (e.g., cytarabine, methotrexate, 5- fluorouracil, enocitabine, and clofarabine), vinca alkaloids (e.g., etoposide, vinblastine, and 59057274.1vincristine), other chemotherapeutic agents such as cisplatin, procarbazine, hydroxyurea, azacytidine, irinotecan, interferon α, interleukin-2, oxaliplatin, carboplatin, nedaplatin, and miriplatin; (ii) opioid analgesics (e.g., morphine); (iii) dopamine receptor D1D2 agonists (e.g., apomorphine); (iv) cannabis and cannabinoid products including cannabis hyperemesis syndrome; (3) Vomiting or nausea caused by radiation sickness or radiation therapy for the chest, the abdomen, or the like used to treat cancers; (4) Vomiting or nausea caused by a poisonous substance or a toxin; (5) Vomiting and nausea caused by pregnancy including hyperemesis gravidarium; (6) Vomiting and nausea caused by a vestibular disorder such as motion sickness or dizziness; (7) Opioid withdrawal; (8) A vestibular disorder such as motion sickness or dizziness; and (9) A physical injury causing local, systemic, acute or chronic pain.

[0122] In some embodiments, the emesis is a result of cyclic vomiting syndrome orchemotherapy.

[0123] In some embodiments, the subject is a non-type 2 diabetes mellitus subject.

[0124] In some embodiments, the emesis is delayed emesis or anticipatory emesis.

[0125] In some embodiments, provided herein are methods of treating emesis, with an59057274.1improved profile.

[0126] In some embodiments, the emesis is treated in the subject without inducing anxiety orsedation in the subject.

[0127] In some embodiments, the emesis is treated in the subject without inducing suppressionof glucagon secretion when plasma glucose levels are above fasting levels.

[0128] In some embodiments, the emesis is treated in the subject without substantiallyactivating the GLP-1 receptor.

[0129] In some embodiments, the emesis is treated in the subject without concomitant,subsequent, or prior administration of a GLP-1 receptor agonist.

[0130] In some embodiments, the emesis is treated in a subject not taking a medicament tocontrol a metabolic syndrome disorder.

[0131] In some embodiments, the emesis is treated in a subject taking a medicament to controla metabolic syndrome disorder.

[0132] In some embodiments, the metabolic syndrome disorder is type 2 diabetes mellitus orobesity.

[0133] In some embodiments, the emesis is caused by or causes cyclic vomiting syndrome, ornausea or vomiting associated with chemotherapy. 59057274.1

[0134] In some embodiments, the chemotherapy or chemotherapeutic agent can include: (i)alkylating agents (e.g., cyclophosphamide, carmustine, lomustine, chlorambucil, streptozocin, dacarbazine, ifosfamide, temozolomide, busulfan, bendamustine, and melphalan), cytotoxic antibiotics (e.g., dactinomycin, doxorubicin, mitomycin-C, bleomycin, epirubicin, actinomycin D, amrubicin, idarubicin, daunorubicin, and pirarubicin), antimetabolic agents (e.g., cytarabine, methotrexate, 5-fluorouracil, enocitabine, and clofarabine), vinca alkaloids (e.g., etoposide, vinblastine, and vincristine), other chemotherapeutic agents such as cisplatin, procarbazine, hydroxyurea, azacytidine, irinotecan, interferon α, interleukin-2, oxaliplatin, carboplatin, nedaplatin, and miriplatin; (ii) opioid analgesics (e.g., morphine); (iii) dopamine receptor D1D2 agonists (e.g., apomorphine); (iv) cannabis and cannabinoid products including cannabis hyperemesis syndrome.

[0135] In some embodiments, the subject has type 2 diabetes mellitus.

[0136] In some embodiments, the GIP receptor agonist peptide or medicament is administeredsubcutaneously, intravenously, intramuscularly, intraperitonealy, orally or via inhalation.

[0137] In some embodiments, the GIP receptor agonist peptide or medicament is administeredsubcutaneously.

[0138] In some embodiments, the effective amount of the GIP receptor agonist peptide59057274.1administered to the subject is about 0.01 to 0.5 mg / kg / day, 0.1 to 5 mg / kg / day, 5 to 10 mg / kg / day, 10 to 20 mg / kg / day, 20 to 50 mg / kg / day, 10 to 100 mg / kg / day, 10 to 120 mg / kg / day, 50 to 100 mg / kg / day, 100 to 200 mg / kg / day, 200 to 300 mg / kg / day, 300 to 400 mg / kg / day, 400 to 500 mg / kg / day, 500 to 600 mg / kg / day, 600 to 700 mg / kg / day, 700 to 800 mg / kg / day, 800 to 900 mg / kg / day, or 900 to 1000 mg / kg / day.

[0139] In some embodiments, the subject is human.

[0140] In some embodiments, the GIP receptor agonist peptide or medicament is administeredto the subject before, during, or after the subject develops the emesis, the vomiting, the nausea, or the one or more conditions or causes described herein.

[0141] In some embodiments, the GIP receptor agonist peptide or medicament is administeredto the subject 1 time per day, or 1 time per 24 hours.

[0142] In some embodiments, the GIP receptor agonist peptide or medicament is administeredto the subject for 1-5 days, 1-5 weeks, 1-5 months, or 1-5 years.

[0143] It should be understood that this disclosure is not limited to the particular methodology,protocols, and reagents, etc., described herein and as such can vary. The terminology used herein is for the purpose of describing particular embodiments only, and is not intended to limit the scope of the present disclosure, which is defined solely by the claims. Other features and advantages of 59057274.1the disclosure will be apparent from the following Detailed Description, the drawings, and the claims. DETAILED DESCRIPTION OF THE EMBODIMENTS

[0144] The present disclosure provides a novel class of selective GIP receptor agonists. TheGIP receptor agonist peptide discussed herein can be used in the preparation of a composition or method for the prevention and / or treatment of a medical condition, or disorder, dosed subcutaneously once weekly (QW) for the rescue (e.g., on-demand rescue) and / or maintenance of nausea and vomiting, for example, treating Cyclic Vomiting Syndrome (CVS). The GIP receptor agonist peptide can be administered by any suitable means including parenteral, e.g., subcutaneous injection, intravenously, by inhalation (e.g., nasal spray), topically, or by oral delivery.

[0145] Most G protein-coupled receptors (GPCRs) undergo some degree of internalizationfollowing agonist binding. Internalization can play a role in downregulation of the GPCRs’ ability to signal at the membrane. Additionally, internalized GPCRs can engage novel signaling pathways inaccessible to GPCRs residing on the surface membrane. Thus, internalization of a GPCR in response to a ligand can be considered a form of signaling. GIP receptors exhibit variable internalization in response to an agonist, with some agonists promoting marked internalization and 59057274.1others being inactive.

[0146] It is believed that GIP receptors may also recruit arrestin to the plasma membrane. β-arrestins are multifunctional proteins that downregulate G protein signaling through direct interactions with GPCRs, as well as serving as scaffolds to recruit other signaling complexes to GPCRs.

[0147] The GIPr agonist peptides of Formulae (I), (I-A) and / or (I-B) as disclosed herein, andpharmaceutically acceptable salts thereof, show an improved profile in subjects dosed with the GIPr agonist. A dose can be a physiologically active or pharmacologically active dose. A physiologically active dose is a dose that is characteristic of or appropriate to the healthy or normal functioning of an organism (e.g., a subject, for example, a human). A pharmacologically active dose is a dose that provides an effect (beneficial or adverse) (e.g., beneficial effect) of a drug on living matter (e.g., a subject, for example, a human). In certain embodiments, a GIP receptor agonist peptide or pharmaceutically acceptable salt thereof, is dosed at physiologically active and pharmacologically active doses, (for example, 0.01 to 0.5 mg / kg / day, 0.1 to 5 mg / kg / day, 5 to 10 mg / kg / day (e.g., up to 5mg / kg / day or 1000nmol / kg), 10 to 20 mg / kg / day, 20 to 50 mg / kg / day, 10 to 100 mg / kg / day, 10 to 120 mg / kg / day, 50 to 100 mg / kg / day, 100 to 200 mg / kg / day, 200 to 300 mg / kg / day, 300 to 400 mg / kg / day, 400 to 500 mg / kg / day, 500 to 600 mg / kg / day, 600 to 700 59057274.1mg / kg / day, 700 to 800 mg / kg / day, 800 to 900 mg / kg / day, or 900 to 1000 mg / kg / day), or the human equivalent dose. The methods of the present disclosure permit administration of the GIP receptor agonist peptide or medicament to a subject in need thereof, for 1-5 days, 1-5 weeks, 1-5 months, or 1-5 years, and any time periods there between.

[0148] The definition of each substituent used in the present specification is described in detailin the following. Unless otherwise specified, each substituent has the following definition.

[0149] In the present specification, examples of the “halogen atom” include fluorine, chlorine,bromine, and iodine.

[0150] In the present specification, examples of the “C1-6 alkyl group” include methyl, ethyl,propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, 1-ethylpropyl, hexyl, isohexyl, 1,1-dimethylbutyl, 2,2-dimethylbutyl, 3,3-dimethylbutyl and 2-ethylbutyl.

[0151] In the present specification, examples of the “optionally halogenated C1-6 alkyl group”include a C1-6 alkyl group optionally having 1 to 7, or 1 to 5, halogen atoms. Specific examples thereof include methyl, chloromethyl, difluoromethyl, trichloromethyl, trifluoromethyl, ethyl, 2- bromoethyl, 2,2,2-trifluoroethyl, tetrafluoroethyl, pentafluoroethyl, propyl, 2,2-difluoropropyl, 3,3,3-trifluoropropyl, isopropyl, butyl, 4,4,4-trifluorobutyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, 5,5,5-trifluoropentyl, hexyl and 6,6,6-trifluorohexyl. 59057274.1

[0152] In the present specification, examples of the “C2-6 alkenyl group” include ethenyl, 1-propenyl, 2-propenyl, 2-methyl-1-propenyl, 1-butenyl, 2-butenyl, 3-butenyl, 3-methyl-2-butenyl, 1-pentenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 4-methyl-3-pentenyl, 1-hexenyl, 3-hexenyl and 5- hexenyl.

[0153] In the present specification, examples of the “C2-6 alkynyl group” include ethynyl, 1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl, 3-butynyl, 1-pentynyl, 2-pentynyl, 3-pentynyl, 4- pentynyl, 1-hexynyl, 2-hexynyl, 3-hexynyl, 4-hexynyl, 5-hexynyl and 4-methyl-2-pentynyl.

[0154] In the present specification, examples of the “C3-10 cycloalkyl group” includecyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, bicyclo[2.2.1]heptyl, bicyclo[2.2.2]octyl, bicyclo[3.2.1]octyl and adamantyl.

[0155] In the present specification, examples of the “optionally halogenated C3-10 cycloalkylgroup” include a C3-10cycloalkyl group optionally having 1 to 7, or 1 to 5, halogen atoms. Specific examples thereof include cyclopropyl, 2,2-difluorocyclopropyl, 2,3-difluorocyclopropyl, cyclobutyl, difluorocyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl.

[0156] In the present specification, examples of the “C3-10 cycloalkenyl group” includecyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, cycloheptenyl and cyclooctenyl. 59057274.1

[0157] In the present specification, examples of the “C6-14 aryl group” include phenyl, 1-naphthyl, 2-naphthyl, 1-anthryl, 2-anthryl and 9-anthryl.

[0158] In the present specification, examples of the “C7-16 aralkyl group” include benzyl,phenethyl, naphthylmethyl and phenylpropyl.

[0159] In the present specification, examples of the “C1-6 alkoxy group” include methoxy,ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, tert-butoxy, pentyloxy and hexyloxy.

[0160] In the present specification, examples of the “optionally halogenated C1-6 alkoxygroup” include a C1-6 alkoxy group optionally having 1 to 7, or 1 to 5, halogen atoms. Specific examples thereof include methoxy, difluoromethoxy, trifluoromethoxy, ethoxy, 2,2,2- trifluoroethoxy, propoxy, isopropoxy, butoxy, 4,4,4-trifluorobutoxy, isobutoxy, sec-butoxy, pentyloxy and hexyloxy.

[0161] In the present specification, examples of the “C3-10 cycloalkyloxy group” includecyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy, cycloheptyloxy and cyclooctyloxy.

[0162] In the present specification, examples of the “C1-6 alkylthio group” include methylthio,ethylthio, propylthio, isopropylthio, butylthio, sec-butylthio, tert-butylthio, pentylthio and hexylthio. 59057274.1

[0163] In the present specification, examples of the “optionally halogenated C1-6 alkylthiogroup” include a C1-6alkylthio group optionally having 1 to 7, or 1 to 5, halogen atoms. Specific examples thereof include methylthio, difluoromethylthio, trifluoromethylthio, ethylthio, propylthio, isopropylthio, butylthio, 4,4,4-trifluorobutylthio, pentylthio and hexylthio.

[0164] In the present specification, examples of the “C1-6 alkyl-carbonyl group” include acetyl,propanoyl, butanoyl, 2-methylpropanoyl, pentanoyl, 3-methylbutanoyl, 2-methylbutanoyl, 2,2- dimethylpropanoyl, hexanoyl and heptanoyl.

[0165] In the present specification, examples of the “optionally halogenated C1-6 alkyl-carbonyl group” include a C1-6alkyl-carbonyl group optionally having 1 to 7, or 1 to 5, halogen atoms. Specific examples thereof include acetyl, chloroacetyl, trifluoroacetyl, trichloroacetyl, propanoyl, butanoyl, pentanoyl and hexanoyl.

[0166] In the present specification, examples of the “C1-6 alkoxy-carbonyl group” includemethoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, isobutoxycarbonyl, sec-butoxycarbonyl, tert-butoxycarbonyl, pentyloxycarbonyl and hexyloxycarbonyl.

[0167] In the present specification, examples of the “C6-14 aryl-carbonyl group” includebenzoyl, 1-naphthoyl and 2-naphthoyl. 59057274.1

[0168] In the present specification, examples of the “C7-16 aralkyl-carbonyl group” includephenylacetyl and phenylpropionyl.

[0169] In the present specification, examples of the “5- to 14-membered aromaticheterocyclylcarbonyl group” include nicotinoyl, isonicotinoyl, thenoyl and furoyl.

[0170] In the present specification, examples of the “3- to 14-membered non-aromaticheterocyclylcarbonyl group” include morpholinylcarbonyl, piperidinylcarbonyl and pyrrolidinylcarbonyl.

[0171] In the present specification, examples of the “mono- or di-C1-6 alkyl-carbamoyl group”include methylcarbamoyl, ethylcarbamoyl, dimethylcarbamoyl, diethylcarbamoyl and N-ethyl-N- methylcarbamoyl.

[0172] In the present specification, examples of the “mono- or di-C7-16 aralkyl-carbamoylgroup” include benzylcarbamoyl and phenethylcarbamoyl.

[0173] In the present specification, examples of the “C1-6 alkylsulfonyl group” includemethylsulfonyl, ethylsulfonyl, propylsulfonyl, isopropylsulfonyl, butylsulfonyl, sec-butylsulfonyl and tert-butylsulfonyl.

[0174] In the present specification, examples of the “optionally halogenated C1-6 alkylsulfonylgroup” include a C1-6alkylsulfonyl group optionally having 1 to 7, or 1 to 5, halogen atoms. 59057274.1Specific examples thereof include methylsulfonyl, difluoromethylsulfonyl, trifluoromethylsulfonyl, ethylsulfonyl, propylsulfonyl, isopropylsulfonyl, butylsulfonyl, 4,4,4- trifluorobutylsulfonyl, pentylsulfonyl and hexylsulfonyl.

[0175] In the present specification, examples of the “C6-14 arylsulfonyl group” includephenylsulfonyl, 1-naphthylsulfonyl and 2-naphthylsulfonyl.

[0176] In the present specification, examples of the “substituent” include a halogen atom, acyano group, a nitro group, an optionally substituted hydrocarbon group, an optionally substituted heterocyclic group, an acyl group, an optionally substituted amino group, an optionally substituted carbamoyl group, an optionally substituted thiocarbamoyl group, an optionally substituted sulfamoyl group, an optionally substituted hydroxy group, an optionally substituted sulfanyl (SH) group and an optionally substituted silyl group.

[0177] In the present specification, examples of the “hydrocarbon group” (including“hydrocarbon group” of “optionally substituted hydrocarbon group”) include a C1-6 alkyl group, a C2-6 alkenyl group, a C2-6 alkynyl group, a C3-10 cycloalkyl group, a C3-10 cycloalkenyl group, a C6- 14 aryl group and a C7-16 aralkyl group. 59057274.1

[0178] In the present specification, examples of the “optionally substituted hydrocarbongroup” include a hydrocarbon group optionally having substituent(s) selected from the following substituent group A. Substituent group A can be: (1) a halogen atom, (2) a nitro group, (3) a cyano group, (4) an oxo group, (5) a hydroxy group, (6) an optionally halogenated C1-6alkoxy group, (7) a C6-14aryloxy group (e.g., phenoxy, naphthoxy), (8) a C7-16aralkyloxy group (e.g., benzyloxy), (9) a 5- to 14-membered aromatic heterocyclyloxy group (e.g., pyridyloxy), (10) a 3- to 14-membered non-aromatic heterocyclyloxy group (e.g., morpholinyloxy, piperidinyloxy), (11) a C1-6 alkyl-carbonyloxy group (e.g., acetoxy, propanoyloxy), (12) a C6-14aryl-carbonyloxy group (e.g., benzoyloxy, 1-naphthoyloxy, 2-naphthoyloxy), 59057274.1(13) a C1-6 alkoxy-carbonyloxy group (e.g., methoxycarbonyloxy, ethoxycarbonyloxy, propoxycarbonyloxy, butoxycarbonyloxy), (14) a mono- or di-C1-6alkyl-carbamoyloxy group (e.g., methylcarbamoyloxy, ethylcarbamoyloxy, dimethylcarbamoyloxy, diethylcarbamoyloxy), (15) a C6-14 aryl-carbamoyloxy group (e.g., phenylcarbamoyloxy, naphthylcarbamoyloxy), (16) a 5- to 14-membered aromatic heterocyclylcarbonyloxy group (e.g., nicotinoyloxy), (17) a 3- to 14-membered non-aromatic heterocyclylcarbonyloxy group (e.g., morpholinylcarbonyloxy, piperidinylcarbonyloxy), (18) an optionally halogenated C1-6alkylsulfonyloxy group (e.g., methylsulfonyloxy, trifluoromethylsulfonyloxy), (19) a C6-14arylsulfonyloxy group optionally substituted by a C1-6alkyl group (e.g., phenylsulfonyloxy, toluenesulfonyloxy), (20) an optionally halogenated C1-6 alkylthio group, (21) a 5- to 14-membered aromatic heterocyclic group, (22) a 3- to 14-membered non-aromatic heterocyclic group, (23) a formyl group, (24) a carboxy group, 59057274.1(25) an optionally halogenated C1-6 alkyl-carbonyl group, (26) a C6-14aryl-carbonyl group, (27) a 5- to 14-membered aromatic heterocyclylcarbonyl group, (28) a 3- to 14-membered non-aromatic heterocyclylcarbonyl group, (29) a C1-6 alkoxy-carbonyl group, (30) a C6-14 aryloxy-carbonyl group (e.g., phenyloxycarbonyl, 1-naphthyloxycarbonyl, 2- naphthyloxycarbonyl), (31) a C7-16 aralkyloxy-carbonyl group (e.g., benzyloxycarbonyl, phenethyloxycarbonyl), (32) a carbamoyl group, (33) a thiocarbamoyl group, (34) a mono- or di-C1-6alkyl-carbamoyl group, (35) a C6-14aryl-carbamoyl group (e.g., phenylcarbamoyl), (36) a 5- to 14-membered aromatic heterocyclylcarbamoyl group (e.g., pyridylcarbamoyl, thienylcarbamoyl), (37) a 3- to 14-membered non-aromatic heterocyclylcarbamoyl group (e.g., morpholinylcarbamoyl, piperidinylcarbamoyl), (38) an optionally halogenated C1-6alkylsulfonyl group, 59057274.1(39) a C6-14 arylsulfonyl group, (40) a 5- to 14-membered aromatic heterocyclylsulfonyl group (e.g., pyridylsulfonyl, thienylsulfonyl), (41) an optionally halogenated C1-6alkylsulfinyl group, (42) a C6-14 arylsulfinyl group (e.g., phenylsulfinyl, 1-naphthylsulfinyl, 2-naphthylsulfinyl), (43) a 5- to 14-membered aromatic heterocyclylsulfinyl group (e.g., pyridylsulfinyl, thienylsulfinyl), (44) an amino group, (45) a mono- or di-C1-6alkylamino group (e.g., methylamino, ethylamino, propylamino, isopropylamino, butylamino, dimethylamino, diethylamino, dipropylamino, dibutylamino, N- ethyl-N-methylamino), (46) a mono- or di-C6-14arylamino group (e.g., phenylamino), (47) a 5- to 14-membered aromatic heterocyclylamino group (e.g., pyridylamino), (48) a C7-16 aralkylamino group (e.g., benzylamino), (49) a formylamino group, (50) a C1-6alkyl-carbonylamino group (e.g., acetylamino, propanoylamino, butanoylamino), (51) a (C1-6alkyl)(C1-6alkyl-carbonyl)amino group (e.g., N-acetyl-N-methylamino), 59057274.1(52) a C6-14 aryl-carbonylamino group (e.g., phenylcarbonylamino, naphthylcarbonylamino), (53) a C1-6alkoxy-carbonylamino group (e.g., methoxycarbonylamino, ethoxycarbonylamino, propoxycarbonylamino, butoxycarbonylamino, tert-butoxycarbonylamino), (54) a C7-16aralkyloxy-carbonylamino group (e.g., benzyloxycarbonylamino), (55) a C1-6 alkylsulfonylamino group (e.g., methylsulfonylamino, ethylsulfonylamino), (56) a C6-14 arylsulfonylamino group optionally substituted by a C1-6 alkyl group (e.g., phenylsulfonylamino, toluenesulfonylamino), (57) an optionally halogenated C1-6 alkyl group, (58) a C2-6alkenyl group, (59) a C2-6alkynyl group, (60) a C3-10cycloalkyl group, (61) a C3-10cycloalkenyl group, or (62) a C6-14 aryl group.

[0179] The number of the above-mentioned substituents in the “optionally substitutedhydrocarbon group” is, for example, 1 to 5, or 1 to 3. When the number of the substituents is two or more, the respective substituents may be the same or different. 59057274.1

[0180] In the present specification, examples of the “heterocyclic group” (including“heterocyclic group” of “optionally substituted heterocyclic group”) include (i) an aromatic heterocyclic group, (ii) a non-aromatic heterocyclic group and (iii) a 7- to 10-membered bridged heterocyclic group, each containing, as a ring-constituting atom besides carbon atom, 1 to 4 hetero atoms selected from a nitrogen atom, a sulfur atom and an oxygen atom.

[0181] In the present specification, examples of the aromatic heterocyclic group (including “5-to 14-membered aromatic heterocyclic group”) include a 5- to 14-membered (or 5- to 10- membered) aromatic heterocyclic group containing, as a ring-constituting atom besides carbon atom, 1 to 4 hetero atoms selected from a nitrogen atom, a sulfur atom and an oxygen atom. Examples of the aromatic heterocyclic group include 5- or 6-membered monocyclic aromatic heterocyclic groups such as thienyl, furyl, pyrrolyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, 1,2,4-oxadiazolyl, 1,3,4- oxadiazolyl, 1,2,4-thiadiazolyl, 1,3,4-thiadiazolyl, triazolyl, tetrazolyl, triazinyl and the like; and 8- to 14-membered fused polycyclic (e.g., bi or tricyclic) aromatic heterocyclic groups such as benzothiophenyl, benzofuranyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzothiazolyl, benzisothiazolyl, benzotriazolyl, imidazopyridinyl, thienopyridinyl, furopyridinyl, pyrrolopyridinyl, pyrazolopyridinyl, oxazolopyridinyl, thiazolopyridinyl, imidazopyrazinyl, 59057274.1imidazopyrimidinyl, thienopyrimidinyl, furopyrimidinyl, pyrrolopyrimidinyl, pyrazolopyrimidinyl, oxazolopyrimidinyl, thiazolopyrimidinyl, pyrazolotriazinyl, naphtho[2,3- b]thienyl, phenoxathiinyl, indolyl, isoindolyl, 1H-indazolyl, purinyl, isoquinolyl, quinolyl, phthalazinyl, naphthyridinyl, quinoxalinyl, quinazolinyl, cinnolinyl, carbazolyl, β-carbolinyl, phenanthridinyl, acridinyl, phenazinyl, phenothiazinyl, phenoxazinyl and the like.

[0182] Examples of the “non-aromatic heterocyclic group” (including “3- to 14-memberednon-aromatic heterocyclic group”) include a 3- to 14-membered (or 4- to 10-membered) non- aromatic heterocyclic group containing, as a ring-constituting atom besides carbon atom, 1 to 4 hetero atoms selected from a nitrogen atom, a sulfur atom and an oxygen atom. Examples of the non-aromatic heterocyclic group include 3- to 8-membered monocyclic non-aromatic heterocyclic groups such as aziridinyl, oxiranyl, thiiranyl, azetidinyl, oxetanyl, thietanyl, tetrahydrothienyl, tetrahydrofuranyl, pyrrolinyl, pyrrolidinyl, imidazolinyl, imidazolidinyl, oxazolinyl, oxazolidinyl, pyrazolinyl, pyrazolidinyl, thiazolinyl, thiazolidinyl, tetrahydroisothiazolyl, tetrahydrooxazolyl, tetrahydroisooxazolyl, piperidinyl, piperazinyl, tetrahydropyridinyl, dihydropyridinyl, dihydrothiopyranyl, tetrahydropyrimidinyl, tetrahydropyridazinyl, dihydropyranyl, tetrahydropyranyl, tetrahydrothiopyranyl, morpholinyl, thiomorpholinyl, azepanyl, diazepanyl, azepinyl, oxepanyl, azocanyl, diazocanyl and the like; and 9- to 14-membered fused polycyclic 59057274.1(e.g., bi or tricyclic) non-aromatic heterocyclic groups such as dihydrobenzofuranyl, dihydrobenzimidazolyl, dihydrobenzoxazolyl, dihydrobenzothiazolyl, dihydrobenzisothiazolyl, dihydronaphtho[2,3-b]thienyl, tetrahydroisoquinolyl, tetrahydroquinolyl, 4H-quinolizinyl, indolinyl, isoindolinyl, tetrahydrothieno[2,3-c]pyridinyl, tetrahydrobenzazepinyl, tetrahydroquinoxalinyl, tetrahydrophenanthridinyl, hexahydrophenothiazinyl, hexahydrophenoxazinyl, tetrahydrophthalazinyl, tetrahydronaphthyridinyl, tetrahydroquinazolinyl, tetrahydrocinnolinyl, tetrahydrocarbazolyl, tetrahydro-β-carbolinyl, tetrahydroacrydinyl, tetrahydrophenazinyl, tetrahydrothioxanthenyl, octahydroisoquinolyl and the like.

[0183] Examples of the “7- to 10-membered bridged heterocyclic group” include quinuclidinyland 7-azabicyclo[2.2.1]heptanyl.

[0184] Examples of the “nitrogen-containing heterocyclic group” include a “heterocyclicgroup” containing at least one nitrogen atom as a ring-constituting atom.

[0185] Examples of the “optionally substituted heterocyclic group” include a heterocyclicgroup optionally having substituent(s) selected from the aforementioned substituent group A. 59057274.1

[0186] The number of the substituents in the “optionally substituted heterocyclic group” is, forexample, 1 to 3. When the number of the substituents is two or more, the respective substituents may be the same or different.

[0187] Examples of the “acyl group” include a formyl group, a carboxy group, a carbamoylgroup, a thiocarbamoyl group, a sulfino group, a sulfo group, a sulfamoyl group and a phosphono group, each optionally having “1 or 2 substituents selected from a C1-6 alkyl group, a C2-6 alkenyl group, a C3-10 cycloalkyl group, a C3-10 cycloalkenyl group, a C6-14 aryl group, a C7-16 aralkyl group, a 5- to 14-membered aromatic heterocyclic group and a 3- to 14-membered non-aromatic heterocyclic group, each of which optionally has 1 to 3 substituents selected from a halogen atom, an optionally halogenated C1-6alkoxy group, a hydroxy group, a nitro group, a cyano group, an amino group and a carbamoyl group”. For example, an “acyl group” can include a hydrocarbon- sulfonyl group, a heterocyclylsulfonyl group, a hydrocarbon-sulfinyl group and a heterocyclylsulfinyl group. In some embodiments, the hydrocarbon-sulfonyl group can include a hydrocarbon group-bonded sulfonyl group, the heterocyclylsulfonyl group means a heterocyclic group-bonded sulfonyl group, the hydrocarbon-sulfinyl group means a hydrocarbon group-bonded sulfinyl group and the heterocyclylsulfinyl group means a heterocyclic group-bonded sulfinyl group. Examples of the acyl group includes a formyl group, a carboxy group, an acetyl group 59057274.1(“Ac”), a C1-6 alkyl-carbonyl group, a C2-6 alkenyl-carbonyl group (e.g., crotonoyl), a C3-10 cycloalkyl-carbonyl group (e.g., cyclobutanecarbonyl, cyclopentanecarbonyl, cyclohexanecarbonyl, cycloheptanecarbonyl), a C3-10cycloalkenyl-carbonyl group (e.g., 2- cyclohexenecarbonyl), a C6-14aryl-carbonyl group, a C7-16aralkyl-carbonyl group, a 5- to 14- membered aromatic heterocyclylcarbonyl group, a 3- to 14-membered non-aromatic heterocyclylcarbonyl group, a C1-6 alkoxy-carbonyl group, a C6-14 aryloxy-carbonyl group (e.g., phenyloxycarbonyl, naphthyloxycarbonyl), a C7-16 aralkyloxy-carbonyl group (e.g., benzyloxycarbonyl, phenethyloxycarbonyl), a carbamoyl group, a mono- or di-C1-6 alkyl- carbamoyl group, a mono- or di-C2-6alkenyl-carbamoyl group (e.g., diallylcarbamoyl), a mono- or di-C3-10cycloalkyl-carbamoyl group (e.g., cyclopropylcarbamoyl), a mono- or di-C6-14aryl- carbamoyl group (e.g., phenylcarbamoyl), a mono- or di-C7-16aralkyl-carbamoyl group, a 5- to 14- membered aromatic heterocyclylcarbamoyl group (e.g., pyridylcarbamoyl), a thiocarbamoyl group, a mono- or di-C1-6 alkyl-thiocarbamoyl group (e.g., methylthiocarbamoyl, N-ethyl-N- methylthiocarbamoyl), a mono- or di-C2-6 alkenyl-thiocarbamoyl group (e.g., diallylthiocarbamoyl), a mono- or di-C3-10 cycloalkyl-thiocarbamoyl group (e.g., cyclopropylthiocarbamoyl, cyclohexylthiocarbamoyl), a mono- or di-C6-14aryl-thiocarbamoyl group (e.g., phenylthiocarbamoyl), a mono- or di-C7-16aralkyl-thiocarbamoyl group (e.g., 59057274.1benzylthiocarbamoyl, phenethylthiocarbamoyl), a 5- to 14-membered aromatic heterocyclylthiocarbamoyl group (e.g., pyridylthiocarbamoyl), a sulfino group, a C1-6alkylsulfinyl group (e.g., methylsulfinyl, ethylsulfinyl), a sulfo group, a C1-6alkylsulfonyl group, a C6-14arylsulfonyl group, a phosphono group and a mono- or di-C1-6alkylphosphono group (e.g., dimethylphosphono, diethylphosphono, diisopropylphosphono, dibutylphosphono).

[0188] Examples of the “optionally substituted amino group” include an amino groupoptionally having “1 or 2 substituents selected from a C1-6 alkyl group, a C2-6 alkenyl group, a C3- 10 cycloalkyl group, a C6-14 aryl group, a C7-16 aralkyl group, a C1-6 alkyl-carbonyl group, a C6-14 aryl-carbonyl group, a C7-16aralkyl-carbonyl group, a 5- to 14-membered aromatic heterocyclylcarbonyl group, a 3- to 14-membered non-aromatic heterocyclylcarbonyl group, a C1-6alkoxy-carbonyl group, a 5- to 14-membered aromatic heterocyclic group, a carbamoyl group, a mono- or di-C1-6alkyl-carbamoyl group, a mono- or di-C7-16aralkyl-carbamoyl group, a C1-6alkylsulfonyl group and a C6-14 arylsulfonyl group, each of which optionally has 1 to 3 substituents selected from substituent group A”.

[0189] Examples of the optionally substituted amino group include an amino group, a mono-or di-(optionally halogenated C1-6alkyl)amino group (e.g., methylamino, trifluoromethylamino, dimethylamino, ethylamino, diethylamino, propylamino, dibutylamino), a mono- or di-C2-659057274.1alkenylamino group (e.g., diallylamino), a mono- or di-C3-10 cycloalkylamino group (e.g., cyclopropylamino, cyclohexylamino), a mono- or di-C6-14arylamino group (e.g., phenylamino), a mono- or di-C7-16aralkylamino group (e.g., benzylamino, dibenzylamino), a mono- or di- (optionally halogenated C1-6alkyl)-carbonylamino group (e.g., acetylamino, propionylamino), a mono- or di-C6-14 aryl-carbonylamino group (e.g., benzoylamino), a mono- or di-C7-16 aralkyl- carbonylamino group (e.g., benzylcarbonylamino), a mono- or di-5- to 14-membered aromatic heterocyclylcarbonylamino group (e.g., nicotinoylamino, isonicotinoylamino), a mono- or di-3- to 14-membered non-aromatic heterocyclylcarbonylamino group (e.g., piperidinylcarbonylamino), a mono- or di-C1-6alkoxy-carbonylamino group (e.g., tert-butoxycarbonylamino), a 5- to 14- membered aromatic heterocyclylamino group (e.g., pyridylamino), a carbamoylamino group, a (mono- or di-C1-6alkyl-carbamoyl)amino group (e.g., methylcarbamoylamino), a (mono- or di-C7-16aralkyl-carbamoyl)amino group (e.g., benzylcarbamoylamino), a C1-6alkylsulfonylamino group (e.g., methylsulfonylamino, ethylsulfonylamino), a C6-14 arylsulfonylamino group (e.g., phenylsulfonylamino), a (C1-6 alkyl)(C1-6 alkyl-carbonyl)amino group (e.g., N-acetyl-N- methylamino) and a (C1-6 alkyl)(C6-14 aryl-carbonyl)amino group (e.g., N-benzoyl-N- methylamino). 59057274.1

[0190] Examples of the optionally substituted carbamoyl group include a carbamoyl groupoptionally having “1 or 2 substituents selected from a C1-6alkyl group, a C2-6alkenyl group, a C3-10cycloalkyl group, a C6-14aryl group, a C7-16aralkyl group, a C1-6alkyl-carbonyl group, a C6-14aryl-carbonyl group, a C7-16aralkyl-carbonyl group, a 5- to 14-membered aromatic heterocyclylcarbonyl group, a 3- to 14-membered non-aromatic heterocyclylcarbonyl group, a C1- 6 alkoxy-carbonyl group, a 5- to 14-membered aromatic heterocyclic group, a carbamoyl group, a mono- or di-C1-6 alkyl-carbamoyl group and a mono- or di-C7-16 aralkyl-carbamoyl group, each of which optionally has 1 to 3 substituents selected from substituent group A”.

[0191] Examples of the optionally substituted carbamoyl group include a carbamoyl group, amono- or di-C1-6alkyl-carbamoyl group, a mono- or di-C2-6alkenyl-carbamoyl group (e.g., diallylcarbamoyl), a mono- or di-C3-10cycloalkyl-carbamoyl group (e.g., cyclopropylcarbamoyl, cyclohexylcarbamoyl), a mono- or di-C6-14aryl-carbamoyl group (e.g., phenylcarbamoyl), a mono- or di-C7-16 aralkyl-carbamoyl group, a mono- or di-C1-6 alkyl-carbonyl-carbamoyl group (e.g., acetylcarbamoyl, propionylcarbamoyl), a mono- or di-C6-14 aryl-carbonyl-carbamoyl group (e.g., benzoylcarbamoyl) and a 5- to 14-membered aromatic heterocyclylcarbamoyl group (e.g., pyridylcarbamoyl). 59057274.1

[0192] Examples of the optionally substituted thiocarbamoyl group include a thiocarbamoylgroup optionally having “1 or 2 substituents selected from a C1-6alkyl group, a C2-6alkenyl group, a C3-10cycloalkyl group, a C6-14aryl group, a C7-16aralkyl group, a C1-6alkyl-carbonyl group, a C6-14aryl-carbonyl group, a C7-16aralkyl-carbonyl group, a 5- to 14-membered aromatic heterocyclylcarbonyl group, a 3- to 14-membered non-aromatic heterocyclylcarbonyl group, a C1- 6 alkoxy-carbonyl group, a 5- to 14-membered aromatic heterocyclic group, a carbamoyl group, a mono- or di-C1-6 alkyl-carbamoyl group and a mono- or di-C7-16 aralkyl-carbamoyl group, each of which optionally has 1 to 3 substituents selected from substituent group A”.

[0193] Examples of the optionally substituted thiocarbamoyl group include a thiocarbamoylgroup, a mono- or di-C1-6alkyl-thiocarbamoyl group (e.g., methylthiocarbamoyl, ethylthiocarbamoyl, dimethylthiocarbamoyl, diethylthiocarbamoyl, N-ethyl-N- methylthiocarbamoyl), a mono- or di-C2-6alkenyl-thiocarbamoyl group (e.g., diallylthiocarbamoyl), a mono- or di-C3-10 cycloalkyl-thiocarbamoyl group (e.g., cyclopropylthiocarbamoyl, cyclohexylthiocarbamoyl), a mono- or di-C6-14 aryl-thiocarbamoyl group (e.g., phenylthiocarbamoyl), a mono- or di-C7-16 aralkyl-thiocarbamoyl group (e.g., benzylthiocarbamoyl, phenethylthiocarbamoyl), a mono- or di-C1-6alkyl-carbonyl-thiocarbamoyl group (e.g., acetylthiocarbamoyl, propionylthiocarbamoyl), a mono- or di-C6-14aryl-carbonyl- 59057274.1thiocarbamoyl group (e.g., benzoylthiocarbamoyl) and a 5- to 14-membered aromatic heterocyclylthiocarbamoyl group (e.g., pyridylthiocarbamoyl).

[0194] Examples of the optionally substituted sulfamoyl group include a sulfamoyl groupoptionally having “1 or 2 substituents selected from a C1-6alkyl group, a C2-6alkenyl group, a C3-10 cycloalkyl group, a C6-14 aryl group, a C7-16 aralkyl group, a C1-6 alkyl-carbonyl group, a C6-14 aryl-carbonyl group, a C7-16 aralkyl-carbonyl group, a 5- to 14-membered aromatic heterocyclylcarbonyl group, a 3- to 14-membered non-aromatic heterocyclylcarbonyl group, a C1- 6 alkoxy-carbonyl group, a 5- to 14-membered aromatic heterocyclic group, a carbamoyl group, a mono- or di-C1-6alkyl-carbamoyl group and a mono- or di-C7-16aralkyl-carbamoyl group, each of which optionally has 1 to 3 substituents selected from substituent group A”.

[0195] Examples of the optionally substituted sulfamoyl group include a sulfamoyl group, amono- or di-C1-6alkyl-sulfamoyl group (e.g., methylsulfamoyl, ethylsulfamoyl, dimethylsulfamoyl, diethylsulfamoyl, N-ethyl-N-methylsulfamoyl), a mono- or di-C2-6 alkenyl- sulfamoyl group (e.g., diallylsulfamoyl), a mono- or di-C3-10 cycloalkyl-sulfamoyl group (e.g., cyclopropylsulfamoyl, cyclohexylsulfamoyl), a mono- or di-C6-14 aryl-sulfamoyl group (e.g., phenylsulfamoyl), a mono- or di-C7-16aralkyl-sulfamoyl group (e.g., benzylsulfamoyl, phenethylsulfamoyl), a mono- or di-C1-6alkyl-carbonyl-sulfamoyl group (e.g., acetylsulfamoyl, 59057274.1propionylsulfamoyl), a mono- or di-C6-14 aryl-carbonyl-sulfamoyl group (e.g., benzoylsulfamoyl) and a 5- to 14-membered aromatic heterocyclylsulfamoyl group (e.g., pyridylsulfamoyl).

[0196] Examples of the optionally substituted hydroxy group include a hydroxyl groupoptionally having “a substituent selected from a C1-6alkyl group, a C2-6alkenyl group, a C3-10cycloalkyl group, a C6-14 aryl group, a C7-16 aralkyl group, a C1-6 alkyl-carbonyl group, a C6-14 aryl- carbonyl group, a C7-16 aralkyl-carbonyl group, a 5- to 14-membered aromatic heterocyclylcarbonyl group, a 3- to 14-membered non-aromatic heterocyclylcarbonyl group, a C1-6 alkoxy-carbonyl group, a 5- to 14-membered aromatic heterocyclic group, a carbamoyl group, a mono- or di-C1-6alkyl-carbamoyl group, a mono- or di-C7-16aralkyl-carbamoyl group, a C1-6alkylsulfonyl group and a C6-14arylsulfonyl group, each of which optionally has 1 to 3 substituents selected from substituent group A”.

[0197] Examples of the optionally substituted hydroxy group include a hydroxy group, a C1-6alkoxy group, a C2-6 alkenyloxy group (e.g., allyloxy, 2-butenyloxy, 2-pentenyloxy, 3- hexenyloxy), a C3-10 cycloalkyloxy group (e.g., cyclohexyloxy), a C6-14 aryloxy group (e.g., phenoxy, naphthyloxy), a C7-16 aralkyloxy group (e.g., benzyloxy, phenethyloxy), a C1-6 alkyl- carbonyloxy group (e.g., acetyloxy, propionyloxy, butyryloxy, isobutyryloxy, pivaloyloxy), a C6-14aryl-carbonyloxy group (e.g., benzoyloxy), a C7-16aralkyl-carbonyloxy group (e.g., 59057274.1benzylcarbonyloxy), a 5- to 14-membered aromatic heterocyclylcarbonyloxy group (e.g., nicotinoyloxy), a 3- to 14-membered non-aromatic heterocyclylcarbonyloxy group (e.g., piperidinylcarbonyloxy), a C1-6alkoxy-carbonyloxy group (e.g., tert-butoxycarbonyloxy), a 5- to 14-membered aromatic heterocyclyloxy group (e.g., pyridyloxy), a carbamoyloxy group, a C1-6alkyl-carbamoyloxy group (e.g., methylcarbamoyloxy), a C7-16 aralkyl-carbamoyloxy group (e.g., benzylcarbamoyloxy), a C1-6 alkylsulfonyloxy group (e.g., methylsulfonyloxy, ethylsulfonyloxy) and a C6-14 arylsulfonyloxy group (e.g., phenylsulfonyloxy).

[0198] Examples of the optionally substituted sulfanyl group include a sulfanyl groupoptionally having “a substituent selected from a C1-6alkyl group, a C2-6alkenyl group, a C3-10cycloalkyl group, a C6-14aryl group, a C7-16aralkyl group, a C1-6alkyl-carbonyl group, a C6-14aryl- carbonyl group and a 5- to 14-membered aromatic heterocyclic group, each of which optionally has 1 to 3 substituents selected from substituent group A” and a halogenated sulfanyl group.

[0199] Examples of the optionally substituted sulfanyl group include a sulfanyl (-SH) group,a C1-6 alkylthio group, a C2-6 alkenylthio group (e.g., allylthio, 2-butenylthio, 2-pentenylthio, 3- hexenylthio), a C3-10 cycloalkylthio group (e.g., cyclohexylthio), a C6-14 arylthio group (e.g., phenylthio, naphthylthio), a C7-16aralkylthio group (e.g., benzylthio, phenethylthio), a C1-6alkyl- carbonylthio group (e.g., acetylthio, propionylthio, butyrylthio, isobutyrylthio, pivaloylthio), a C6-59057274.114 aryl-carbonylthio group (e.g., benzoylthio), a 5- to 14-membered aromatic heterocyclylthio group (e.g., pyridylthio) and a halogenated thio group (e.g., pentafluorothio).

[0200] Examples of the “optionally substituted silyl group” include a silyl group optionallyhaving “1 to 3 substituents selected from a C1-6alkyl group, a C2-6alkenyl group, a C3-10cycloalkyl group, a C6-14 aryl group and a C7-16 aralkyl group, each of which optionally has 1 to 3 substituents selected from substituent group A”.

[0201] Examples of the optionally substituted silyl group include a tri-C1-6 alkylsilyl group(e.g., trimethylsilyl, tert-butyl(dimethyl)silyl).

[0202] For descriptions of amino acid residues, the following conventions may beexemplified:Asp=D=Aspartic Acid; Ala=A=Alanine; Arg=R=Arginine; Asn=N=Asparagine; Cys=C=Cysteine; Gly=G=Glycine; Glu=E=Glutamic Acid; Gln=Q=Glutamine; His=H=Histidine; Ile=I=Isoleucine; Leu=L=Leucine; Lys=K=Lysine; Met=M=Methionine; Phe=F=Phenylalanine; Pro=P=Proline; Ser=S=Serine; Thr=T=Threonine; Trp=W=Tryptophan; Tyr=Y=Tyrosine; and Val=V=Valine.

[0203] Also for convenience, and readily known to one skilled in the art, the followingabbreviations or symbols are used to represent the moieties, reagents and the like used in present disclosure: 59057274.1

[0204] Aib: alpha-aminoisobutyric acid;

[0205] mono-halo Phe: mono-halo phenylalanine;

[0206] bis-halo Phe: bis-halo phenylalanine;

[0207] mono-halo Tyr: mono-halo tyrosine;

[0208] bis-halo Tyr: bis-halo Tyrosine;

[0209] (D)-Tyr: D-tyrosine;

[0210] (D)-Ala:- D-Alanine;

[0211] DesNH2-Tyr: desaminotyrosine;

[0212] (D)-Phe: D-phenylalanine;

[0213] DesNH2-Phe:desaminophenylalanine;

[0214] (D)-Trp: D-tryptophan;

[0215] (D)3Pya: D-3-pyridylalanine;

[0216] 2-Cl-(D)Phe: D-2-chlorophenylalanine;

[0217] 3-Cl-(D)Phe: D-3-chlorophenylalanine;

[0218] 4-Cl-(D)Phe:D-4-chlorophenylalanine;

[0219] 2-F-(D)Phe: D-2-fluorophenylalanine;

[0220] 3-F(D)Phe: D-3-fluorophenylalanine;59057274.1

[0221] 3,5-DiF-(D)Phe: D-3,5-difluorophenylalanine;

[0222] 3,4,5-TriF-(D)Phe: D-3,4,5-trifluorophenylalanine;

[0223] D-Iva: D-Isovaline;

[0224] SSA: succinimidyl succinamide;

[0225] PEG: polyethylene glycol;

[0226] PEGm: (methoxy)polyethylene glycol;

[0227] PEGm(12,000): (methoxy)polyethylene glycol having a molecular weight of about 12kD;

[0228] PEGm(20,000): (methoxy)polyethylene glycol having a molecular weight of about 20kD;

[0229] PEGm(30,000): (methoxy)polyethylene glycol having a molecular weight of about 30kD;

[0230] Fmoc: 9-fluorenylmethyloxycarbonyl;

[0231] DMF: dimethylformamide;

[0232] DIPEA: N,N-diisopropylethylamine;

[0233] TFA: trifluoroacetic acid;

[0234] HOBT: N-hydroxybenzotriazole;59057274.1

[0235] BOP: benzotriazol-1-yloxy-tris-(dimethylamino)phosphonium-hexafluorophosphate;

[0236] HBTU: 2-(1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluronium-hexafluorophosphate;

[0237] NMP: N-methyl-pyrrolidone;

[0238] FAB-MS: fast atom bombardment mass spectrometry;

[0239] ES-MS: electro spray mass spectrometry.

[0240] Abu: α-aminobutyric acid;

[0241] Acc: 1-amino-1-cyclo(C3-C9)alkyl carboxylic acid;

[0242] A3c: 1-amino-1-cyclopropane carboxylic acid;

[0243] A4c: 1-amino-1-cyclobutanecarboxylic acid;

[0244] A5c: 1-amino-1-cyclopentanecarboxylic acid;

[0245] A6c: 1-amino-1-cyclohexanecarboxylic acid;

[0246] Act: 4-amino-4-carboxytetrahydropyran;

[0247] Ado: 12-aminododecanoic acid;

[0248] Aib: alpha-aminoisobutyric acid;

[0249] Aic: 2-aminoindan-2-carboxylic acid;

[0250] β-Ala: beta-alanine;

[0251] Amp: 4-amino-phenylalanine;59057274.1

[0252] Apc: 4-amino-4-carboxypiperidine;

[0253] hArg: homoarginine;

[0254] Aun: 11-aminoundecanoic acid;

[0255] Ava: 5-aminovaleric acid;

[0256] Cha: β-cyclohexylalanine;

[0257] Dhp: 3,4-dehydroproline;

[0258] Dmt: 5,5-dimethylthiazolidine-4-carboxylic acid;

[0259] Gaba: γ-aminobutyric acid;

[0260] 4Hppa: 3-(4-hydroxyphenyl)propionic acid;

[0261] Hyp: hydroxyproline

[0262] 3Hyp: 3-hydroxyproline;

[0263] 4Hyp: 4-hydroxyproline;

[0264] hPro: homoproline;

[0265] 4Ktp: 4-ketoproline;

[0266] Nle: norleucine;

[0267] NMe-Tyr: N-methyl-tyrosine;

[0268] 1Nal or 1-Nal: β-(1-naphthyl)alanine;59057274.1

[0269] 2Nal or 2-Nal: β-(2-naphthyl)alanine;

[0270] Nva: norvaline;

[0271] Orn: ornithine;

[0272] 2Pal or 2-Pal: β-(2-pyridinyl)alanine;

[0273] 3Pal or 3-Pal: β-(3-pyridinyl)alanine;

[0274] 4Pal or 4-Pal: β-(4-pyridinyl)alanine;

[0275] Pen: penicillamine;

[0276] (3,4,5F)Phe: 3,4,5-trifluorophenylalanine;

[0277] (2,3,4,5,6)Phe: 2,3,4,5,6-pentafluorophenylalanine;

[0278] Psu: N-propylsuccinimide;

[0279] Iva: Isovaline;

[0280] Sar: Sarcosine;

[0281] Taz: β-(4-thiazolyl)alanine;

[0282] 3Thi: β-(3-thienyl)alanine;

[0283] Thz: thioproline;

[0284] Tic: tetrahydroisoquinoline-3-carboxylic acid;

[0285] Tle: tert-leucine;59057274.1

[0286] Act: acetonitrile;

[0287] Boc: tert-butyloxycarbonyl;

[0288] BSA: bovine serum albumin;

[0289] DCM: dichloromethane;

[0290] DTT: dithiothrieitol;

[0291] ESI: electrospray ionization;

[0292] Fmoc: 9-fluorenylmethyloxycarbonyl;

[0293] HBTU: 2-(1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate;

[0294] HPLC: high performance liquid chromatography;

[0295] IBMX: isobutylmethylxanthine;

[0296] LC-MS: liquid chromatography-mass spectrometry;

[0297] Mtt: methyltrityl;

[0298] NMP: N-methylpyrrolidone;

[0299] 5K PEG: polyethylene glycol, which may include other functional groups or moietiessuch as a linker, and which is either linear or branched as defined herein below, with a weight average molecular weight of about 5,000 Daltons; 59057274.1

[0300] 10K PEG: polyethylene glycol, which may include other functional groups ormoieties such as a linker, and which is either linear or branched as defined herein below, with a weight average molecular weight of about 10,000 Daltons;

[0301] 20K PEG: polyethylene glycol, which may include other functional groups ormoieties such as a linker, and which is either linear or branched as defined herein below, with a weight average molecular weight of about 20,000 Daltons;

[0302] 30K PEG: polyethylene glycol, which may include other functional groups ormoieties such as a linker, and which is either linear or branched as defined herein below, with a weight average molecular weight of about 30,000 Daltons;

[0303] 40K PEG: polyethylene glycol, which may include other functional groups ormoieties such as a linker, and which is either linear or branched as defined herein below, with a weight average molecular weight of about 40,000 Daltons;

[0304] 50K PEG: polyethylene glycol, which may include other functional groups ormoieties such as a linker, and which is either linear or branched as defined herein below, with a weight average molecular weight of about 50,000 Daltons; 59057274.1

[0305] 60K PEG: polyethylene glycol, which may include other functional groups ormoieties such as a linker, and which is either linear or branched as defined herein below, with a weight average molecular weight of about 60,000 Daltons; tBu: tert-butyl;

[0306] TIS: triisopropylsilane;

[0307] Trt: trityl; and

[0308] Z: benzyloxycarbonyl.

[0309] PEG is available in a variety of molecular weights based on the number of repeatingsubunits of ethylene oxide (i.e. —OCH2CH2—) within the molecule.PEG formulations are usually followed by a number that corresponds to their average molecular weight. For example, PEG-200 has a weight average molecular weight of 200 Daltons and may have a molecular weight range of 190-210 Daltons. Molecular weight in the context of a water-soluble polymer, such as PEG, can be expressed as either a number average molecular weight or a weight average molecular weight. Unless otherwise indicated, all references to molecular weight of PEG herein refer to the weight average molecular weight. Both molecular weight determinations, number average and weight average, can be measured using gel permeation chromatography or other liquid chromatography techniques. Other methods for measuring molecular weight values can also be used, such as the use of end-group analysis or the measurement of colligative properties (e.g., freezing-point 59057274.1depression, boiling-point elevation, or osmotic pressure) to determine number average molecular weight or the use of light scattering techniques, ultracentrifugation or viscometry to determine weight average molecular weight.

[0310] As used herein, "PEG moiety" refers to polyethylene glycol (PEG) or a derivativethereof, for example (methoxy)polyethylene glycol (mPEG).

[0311] As used herein, "PEGylated peptide" refers to a peptide wherein at least one amino acidresidue, for example, Lys, or Cys has been conjugated with a PEG moiety. By "conjugated", it is meant that the PEG moiety is either directly linked to said residue or is linked to the residue via a spacer moiety, for example a cross-linking agent. When said conjugation is at a lysine residue, that lysine residue is referred to herein as "PEGylated Lys". A peptide that is conjugated to only one PEG moiety is said to be "mono-PEGylated".

[0312] As used herein, "Lys-PEG" and "Lys-PEGm" refer respectively to lysine residues whichhave been conjugated with PEG. "Lys(epsilon-SSA-PEGn)" refers to a lysine residue wherein the epsilon-amino group has been cross-linked with MPEG using a suitably functionalized SSA.

[0313] In the present specification, the term “human native GIP peptide” refers to the naturallyoccurring human GIP peptide. This human native GIP peptide (42 amino acids) has an amino acid sequence: YAEGTFISDYSIAMDKIHQQDFVNWLLAQKGKKNDWKHNITQ (SEQ ID NO: 1) 59057274.1and is the functionally active molecule derived from the parent precursor described in National Center for Biotechnology Information (NCBI) Reference Sequence: NP_004114.1; REFSEQ: accession NM_004123.2 This full length precursor is encoded from the mRNA sequence of human gastric inhibitory polypeptide (GIP), mRNA; ACCESSION: NM_004123; VERSION; NM_004123.2.

[0314] "Percent (%) amino acid sequence identity" with respect to a reference polypeptidesequence is defined as the percentage of amino acid residues in a candidate polypeptide sequence that are identical with the amino acid residues in the reference polypeptide sequence, after aligning the sequences and introducing gaps, if necessary, to achieve the maximum percent sequence identity, and not considering any conservative substitutions as part of the sequence identity. Alignment for purposes of determining percent amino acid sequence identity can be achieved in various ways that are within the skill in the art, for instance, using publicly available computer software such as BLAST, BLAST-2, ALIGN or Megalign (DNASTAR) software. Those skilled in the art can determine appropriate parameters for aligning sequences, including any algorithms needed to achieve maximal alignment over the full length of the sequences being compared.

[0315] As used herein, "treatment" (and variations such as "treat" or "treating") refers toclinical intervention in an attempt to alter the natural course of the individual being treated, and 59057274.1can be performed either for prophylaxis or during the course of clinical pathology. Desirable effects of treatment include, but are not limited to, preventing occurrence or recurrence of a condition, alleviation of symptoms, diminishment of any direct or indirect pathological consequences of the condition or treatment, preventing emesis, i.e., by preventing the occurrence of symptoms in whole or in part associated with a condition or side-effects known to accompany a specific treatment, decreasing the rate of progression, amelioration or palliation of the symptoms associated with emesis, such as nausea and / or vomiting, and remission or improved prognosis. In some embodiments, GIP receptor agonist peptides of the disclosure are used to inhibit or delay development of emesis, i.e. nausea or vomiting or to slow the progression of emesis or the symptoms associated with emesis, or to prevent, delay or inhibit the development of emesis, nausea and / or vomiting related to the treatment of a different disease being actively treated.

[0316] By "reduce" or "inhibit" is meant the ability to cause an overall decrease of 20%, 30%,40%, 50%, 60%, 70%, 75%, 80%, 85%, 90%, 95%, or greater. In some embodiments, reduce or inhibit can refer to a relative reduction compared to a reference (e.g., reference level of biological activity (e.g., the number of episodes of nausea and / or vomiting after administration to a subject of a prescribed amount of chemotherapy, for example, a prescribed dose of a chemotherapeutic agent that is known to cause emesis). In some embodiments, reduce or inhibit can refer to the 59057274.1relative reduction of a side effect (i.e. nausea and / or vomiting) associated with a treatment for a condition or disease.

[0317] Optimal alignment of sequences for comparison can be conducted, for example, by thelocal homology algorithm of Smith and Waterman (Adv. Appl. Math. 2:482 (1981), which is incorporated by reference herein), by the homology alignment algorithm of Needleman and Wunsch (J. MoI. Biol.48:443-53 (1970), which is incorporated by reference herein), by the search for similarity method of Pearson and Lipman (Proc. Natl. Acad. Sci. USA 85:2444-48 (1988), which is incorporated by reference herein), by computerized implementations of these algorithms (e.g., GAP, BESTFIT, FASTA, and TFASTA in the Wisconsin Genetics Software Package, Genetics Computer Group, 575 Science Dr., Madison, Wis.), or by visual inspection. (See generally Ausubel et al. (eds.), Current Protocols in Molecular Biology, 4th ed., John Wiley and Sons, New York (1999)).

[0318] One illustrative example of an algorithm that is suitable for determining percentsequence identity and sequence similarity is the BLAST algorithm, which is described by Altschul et al. (J. MoI. Biol. 215:403-410 (1990), which is incorporated by reference herein). (See also Zhang et al., Nucleic Acid Res. 26:3986-90 (1998); Altschul et al., Nucleic Acid Res. 25:3389- 402 (1997), which are incorporated by reference herein). Software for performing BLAST 59057274.1analyses is publicly available through the National Center for Biotechnology Information internet web site. This algorithm involves first identifying high scoring sequence pairs (HSPs) by identifying short words of length W in the query sequence, which either match or satisfy some positive-valued threshold score T when aligned with a word of the same length in a database sequence. T is referred to as the neighborhood word score threshold (Altschul et al. (1990), supra). These initial neighborhood word hits act as seeds for initiating searches to find longer HSPs containing them. The word hits are then extended in both directions along each sequence for as far as the cumulative alignment score can be increased. Extension of the word hits in each direction is halted when: the cumulative alignment score falls off by the quantity X from its maximum achieved value; the cumulative score goes to zero or below, due to the accumulation of one or more negative-scoring residue alignments; or the end of either sequence is reached. The BLAST algorithm parameters W, T, and X determine the sensitivity and speed of the alignment. The BLAST program uses as defaults a word length (W) of 11, the BLOSUM62 scoring matrix (see Henikoff and Henikoff, Proc. Natl. Acad. Sci. USA 89:10915-9 (1992), which is incorporated by reference herein) alignments (B) of 50, expectation (E) of 10, M=5, N=-4, and a comparison of both strands. 59057274.1

[0319] In addition to calculating percent sequence identity, the BLAST algorithm alsoperforms a statistical analysis of the similarity between two sequences (see, e.g., Karlin and Altschul, Proc. Natl. Acad. Sci. USA 90:5873-77 (1993), which is incorporated by reference herein). One measure of similarity provided by the BLAST algorithm is the smallest sum probability (P(N)), which provides an indication of the probability by which a match between two nucleotide or amino acid sequences would occur by chance. For example, an amino acid sequence is considered similar to a reference amino acid sequence if the smallest sum probability in a comparison of the test amino acid to the reference amino acid is less than about 0.1, more typically less than about 0.01, and most typically less than about 0.001.

[0320] Variants can also be synthetic, recombinant, or chemically modified polynucleotidesor polypeptides isolated or generated using methods well known in the art. Variants can include conservative or non-conservative amino acid changes, as described below. Polynucleotide changes can result in amino acid substitutions, additions, deletions, fusions and truncations in the polypeptide encoded by the reference sequence. Variants can also include insertions, deletions or substitutions of amino acids, including insertions and substitutions of amino acids and other molecules) that do not normally occur in the peptide sequence that is the basis of the variant, for example but not limited to insertion of ornithine which do not normally occur in human proteins. 59057274.1The term "conservative substitution," when describing a polypeptide, refers to a change in the amino acid composition of the polypeptide that does not substantially alter the polypeptide's activity. For example, a conservative substitution refers to substituting an amino acid residue for a different amino acid residue that has similar chemical properties. Conservative amino acid substitutions include replacement of a leucine with an isoleucine or valine, an aspartate with a glutamate, or a threonine with a serine.

[0321] "Conservative amino acid substitutions" as referenced herein result from replacing oneamino acid with another having similar structural and / or chemical properties, such as the replacement of a leucine with an isoleucine or valine, an aspartate with a glutamate, or a threonine with a serine. Thus, a "conservative substitution" of a particular amino acid sequence refers to substitution of those amino acids that are not critical for polypeptide activity or substitution of amino acids with other amino acids having similar properties (e.g., acidic, basic, positively or negatively charged, polar or non-polar, etc.) such that the substitution of even critical amino acids does not reduce the activity of the peptide, (i.e. the ability of the peptide to penetrate the blood brain barrier (BBB)). Conservative substitution tables providing functionally similar amino acids are well known in the art. For example, the following six groups each contain amino acids that are conservative substitutions for one another: 1) Alanine (A), Serine (S), Threonine (T); 2) Aspartic 59057274.1acid (D), Glutamic acid (E); 3) Asparagine (N), Glutamine (Q); 4) Arginine (R), Lysine (K); 5) Isoleucine (I), Leucine (L), Methionine (M), Valine (V); and 6) Phenylalanine (F), Tyrosine (Y), Tryptophan (W). (See also Creighton, Proteins, W. H. Freeman and Company (1984), incorporated by reference in its entirety.) In some embodiments, individual substitutions, deletions or additions that alter, add or delete a single amino acid or a small percentage of amino acids can also be considered "conservative substitutions" if the change does not reduce the activity of the peptide. Insertions or deletions are typically in the range of about 1 to 5 amino acids. The choice of conservative amino acids may be selected based on the location of the amino acid to be substituted in the peptide, for example if the amino acid is on the exterior of the peptide and expose to solvents, or on the interior and not exposed to solvents.

[0322] In alternative embodiments, one can also select conservative amino acid substitutionsencompassed suitable for amino acids on the interior of a protein or peptide, for example one can use suitable conservative substitutions for amino acids is on the interior of a protein or peptide (i.e., the amino acids are not exposed to a solvent), for example but not limited to, one can use the following conservative substitutions: where Y is substituted with F, T with A or S, I with L or V, W with Y, M with L, N with D, G with A, T with A or S, D with N, I with L or V, F with Y or L, 59057274.1S with A or T and A with S, G, T or V. In some embodiments, non-conservative amino acid substitutions are also encompassed within the term of variants.

[0323] As used herein, the term "selectivity" of a molecule for a first receptor relative to asecond receptor refers to the following ratio: EC50of the molecule at the second receptor divided by the EC50 of the molecule at the first receptor. For example, a molecule that has an EC50 of 1 nM at a first receptor and an EC50 of 100 nM at a second receptor has 100-fold selectivity for the first receptor relative to the second receptor. EC50 is the concentration required to obtain 50% of an effect or response.

[0324] As is understood by one skilled in the art, reference to "about" a value or parameterherein includes (and describes) embodiments that are directed to that value or parameter per se or that have a variance plus or minus of that value ranging from less than 10%, or less than 9%, or less than 8%, or less 7%, or less than 6%, or less than 5%, or less than 4%, or less than 3%, or less than 2%, or less than 1%, or less than 0.1 % than the stated value. For example, description referring to "about X" includes description of "X".

[0325] It is understood that aspect and embodiments of the disclosure described herein include"consisting" and / or "consisting essentially" of aspects and embodiments. As used herein, the singular form "a", "an", and "the" includes plural references unless indicated otherwise. 59057274.1

[0326] A. GIP RECEPTOR AGONIST PEPTIDES

[0327] In various embodiments of the present disclosure, GIP receptor agonist peptides areprovided. In addition, methods are provided for the prevention and / or treatment of diabetes mellitus (e.g., type-2 diabetes mellitus) obesity, a metabolic syndrome and emesis in a subject in need thereof. In various embodiments, the methods provide administration of a therapeutically effective amount of a GIP receptor agonist peptide once per week or QW (for example, Q1W, used interchangeably herein) to the subject.

[0328] As used herein, GIPr agonist peptides of the present disclosure refer to peptides thatpreferentially bind to GIP receptors compared to other receptors, such as GLP receptors. In some embodiments, an exemplary GIPr agonist peptide of the present disclosure are GIPr agonist peptides that have a selectivity ratio as defined as the ratio of (EC50GLP1R / EC50GIPR) greater than 10, or greater than 100, or greater than 1,000, or greater than 10,000, or greater than 100,000. An exemplary GIP receptor agonist peptide is a GIPr agonist peptide when the peptide has a selectivity ratio of (EC50 GLP1R / EC50 GIPR) of greater than 10, or 100, or 1,000, or 10,000, or 100,000, or from about 100 to about 1,000,000 or more.

[0329] As used herein, “Lys(R)” is synonymous with “Km,” and these terms are usedinterchangeably. 59057274.1

[0330] In some embodiments, a GIP receptor agonist peptide, or a salt thereof is provided. Insome embodiments, the GIP receptor agonist peptide, or the pharmaceutically acceptable salt thereof, has at least 30 amino acid residues. In some embodiments, the GIP receptor agonist peptide or the pharmaceutically acceptable salt thereof has at least 30 amino acid residues or at least 32 amino acid residues, e.g., 30-40 amino acid residues. In some embodiments, the GIP receptor agonist peptide or the pharmaceutically acceptable salt thereof has at least 32 amino acid residues. In some embodiments, the GIP receptor agonist peptide, or the pharmaceutically acceptable salt thereof, has at least 32 amino acid residues. In some embodiments, the GIP receptor agonist peptide, or the pharmaceutically acceptable salt thereof, has at least 34 amino acid residues. In some embodiments, the GIP receptor agonist peptide, or the pharmaceutically acceptable salt thereof, has at least 36 amino acid residues. In some embodiments, the GIP receptor agonist peptide, or the pharmaceutically acceptable salt thereof, has at least 38 amino acid residues. In some embodiments, the GIP receptor agonist peptide, or the pharmaceutically acceptable salt thereof, has at least 40 amino acid residues. In some embodiments, the GIP receptor agonist peptide, or the pharmaceutically acceptable salt thereof, is a GIP receptor agonist peptide which has 30-40 amino acid residues. In some embodiments, the GIP receptor agonist peptide, or the pharmaceutically acceptable salt thereof, is a GIP receptor agonist peptide which has 32-40 amino 59057274.1acid residues. In some embodiments, the GIP receptor agonist peptide, or the pharmaceutically acceptable salt thereof has, for example, 30 amino acid residues, or 32 residues, or 33 residues, or 34 residues, or 35 residues, or 36 residues, or 37 residues, or 38 residues, or 39 residues, or 40 residues in length. In various embodiments, the GIP receptor agonist peptide, or the pharmaceutically acceptable salt thereof, is a GIP receptor agonist peptide which has 39 amino acid residues, some of which are natural amino acids and some of which, for example at least 3 are unnatural amino acids. In some embodiments, the GIP receptor agonist peptide, or the pharmaceutically acceptable salt thereof, is a GIP receptor agonist peptide, or a pharmaceutically acceptable salt thereof, which has 39 amino acid residues, of which, 3 are unnatural amino acids, for example, each of the three unnatural amino acids is Aib.

[0331] With reference to the GIP receptor agonist peptides as defined by Formulae (I), (I-A)and / or (I-B), in various embodiments, a GIP receptor agonist peptide has at least one amino acid side chain with a covalently attached bivalent substituent. For example, in some embodiments, a GIP receptor agonist peptide, or a pharmaceutically acceptable salt thereof, has an amino acid sequence having a side chain of at least one amino acid, or modified amino acid for example, a Lys residue of the GIP receptor agonist peptide being covalently attached to a substituent group 59057274.1(R). In various embodiments, a Lys residue of the GIP receptor agonist peptide may be covalently attached to a substituent (R) as shown in the present disclosure as Lys(R).

[0332] For example, a selective GIP receptor agonist peptide of the present disclosure mayhave a Lys residue substituted by an (R) group at an amino acid position A14-A30, for example, at amino acid position: A14, A17, A18, A20, A21, A24, A28, A29, or A30 (e.g., at amino acid position A14, A17, A21, A24, or A30). In various embodiments, the (R) group represents X-L-, wherein L represents a bivalent linker. In some embodiments, the bivalent linker can include a PEG, Abu-, (Gly)(2-8)-, OEGgE, 2OEG, 2OEGgE, 2OEGgEgE, 2OEGgEgEgE, 3OEGgE, 3OEGgEgE, G2E3, G3gEgE, G4E2, G4gE, G4gEgE, GGGGG, G5E, G5gE, G5gEgE, gE, gEgEgE, GGEEE, GGPAPAP, OEGgEgE, and OEGgEgEgE, GGPAPAP, one to ten amino acids, for example, a glycine linker having two to ten glycine residues, two to six or from five to six glycines linked, or combinations of the foregoing linkers. In these embodiments, X represents a substituent group, for example, a lipid. In various embodiments, X represents a monoacid or diacid lipid having C17 to C22 carbons in length, for example, a C17, a C18, a C19, a C20, a C21 or a C22 monoacid or diacid lipid. In various embodiments, X represents a monoacid or diacid lipid having C17to C22carbons in length, for example, a C17, a C18, a C19, a C20, a C21,or a C22monoacid or diacid lipid. In various embodiments, X represents a monoacid or diacid lipid having C17to C2259057274.1carbons in length, for example, a C17, a C18, a C19, a C20, C21 or a C22 monoacid or diacid lipid. In some embodiments, X is a C17diacid, a C18diacid, a C19diacid, a C20diacid, a C22diacid or a C22diacid. In some embodiments, X is a C17diacid or C18diacid. In some embodiments, X is a C18diacid.

[0333] In some embodiments, X is a C17 monoacid. In some embodiments, X is a C18monoacid. In some embodiments, X is a C19 monoacid. In some embodiments, X is a C20 monoacid. In some embodiments, X is a C17 diacid (Da). In some embodiments, X is a C18Da. In some embodiments, X is a C19Da. In some embodiments, X is C17 monoacid, C18 monoacid, C19monoacid, C20monoacid, C21diacid (Da), or C22diacid. In some embodiments, X is a C17- C22diacid. In some embodiments, X is a C17-C20diacid. In some embodiments, X is a C17diacid, C18diacid, C19diacid, C20diacid, or C21diacid.

[0334] In various embodiments, the GIP receptor agonist peptide may include one or two Lysresidues substituted with an X-L- substituent. In some embodiments, a Lys residue is substituted with an X-L- substituent, wherein L represents (PEG, Abu-, (Gly)(2-8)-, gGlu(1-3)-, gE, GGGGG, GGEEE, G2E3, G3gEgE, OEGgE, 2OEG, 2OEGgE, 2OEGgEgE, 2OEGgEgEgE, 3OEGgE, 3OEGgEgE, G3gEgE, G4gE, G4gEgE, GGGGG, G5gE, G5gEgE, OEGgEgE, OEGgEgEgE;, GGPAPAP, one to ten amino acids, for example, a glycine linker having two to ten glycine residues, 59057274.1two to six or from five to six glycines linked, or combinations of the foregoing linkers.

[0335] In various embodiments, the GIP receptor agonist peptide may include one or two Lysresidues substituted with an X-L- substituent. In some embodiments, a Lys residue is substituted with an -L-X substituent, wherein L represents a linker and is selected from the group consisting of OEGgE, 2OEG, 2OEGgE, 2OEG2gE, 2OEGgEgE, 2OEGgEgEgE, 3OEGgE, 3OEGgEgE, G2E3, G3gEgE, G4E2, G4gE, G4gEgE, GGGGG, G5E, G5gE, G5gEgE, gE, gEgEgE, GGEEE, GGPAPAP, OEGgEgE, and OEGgEgEgE, GGPAPAP, one to ten amino acids, for example, a glycine linker having two to ten glycine residues, two to six or from five to six glycines linked, or combinations of the foregoing linkers.

[0336] In various embodiments, the GIP receptor agonist peptide may include one or two Lysresidues substituted with an X-L- substituent. For example, GIP receptor agonist peptides of Formulae (I), (I-A) and / or (I-B) may have a substituted Lys(R) residue at one or two amino acid residue positions selected from: at an amino acid position: A14, A17, A18, A20, A21, AA24, A29, or A30, wherein the Lys(R) amino acid comprises a substituent X-L-, wherein L represents a linker and is selected from the group consisting of 1OEGgE, 2OEG, 2OEGgE, 2OEG2gE, 2OEGgEgE, 2OEGgEgEgE, 3OEGgE, 3OEGgEgE, G2E3, G3gEgE, G4E2, G4gE, G4gEgE, GGGGG, G5E, G5gE, G5gEgE, gE, gEgEgE, GGEEE, GGPAPAP, OEGgEgE, and OEGgEgEgE, GGPAPAP, one 59057274.1to ten amino acids, for example, a glycine linker having two to ten glycine residues, two to six or from five to six glycines linked, or combinations of the foregoing linkers, and X represents an optionally substituted hydrocarbon group, for example a monoacid or diacid lipid, or a salt thereof, for example, X is a C17-C22monoacid, a C17-C22diacid or an acetyl group. Some exemplary X moieties may include: X represents C17-C22 linear saturated dicarboxylic acid.

[0337] In various embodiments, the GIP receptor agonist peptide may include one or two Lysresidues substituted with an X-L- substituent. For example, GIP receptor agonist peptides of Formulae (I), (I-A) and / or (I-B) may have a substituted Lys(R) residue at amino acid position: A21, wherein the Lys(R) amino acid comprises a substituent X-L-, wherein L represents a linker and is selected from the group consisting of 1OEGgE, 2OEG, 2OEGgE, 2OEG2gE, 2OEGgEgE, 2OEGgEgEgE, 3OEGgE, 3OEGgEgE, G2E3, G3gEgE, G4E2, G4gE, G4gEgE, GGGGG, G5E, G5gE, G5gEgE, gE, gEgEgE, GGEEE, GGPAPAP, OEGgEgE, and OEGgEgEgE, GGPAPAP, one to ten amino acids, for example, a glycine linker having two to ten glycine residues, two to six or from five to six glycines linked, or combinations of the foregoing linkers, and X represents an optionally substituted hydrocarbon group, for example a monoacid or diacid lipid, or a salt thereof, for example, X is a C17-C22monoacid, a C17-C22diacid or an acetyl group. Some exemplary X moieties may include: X represents C17-C22linear saturated dicarboxylic acid. 59057274.1

[0338] In some embodiments, the GIP receptor agonist peptide has one, or two Lys residueshaving a substituted side chain. For example, a GIPr agonist peptide of the present disclosure may have a Lys residue substituted by X-L-, wherein L represents a bivalent linker, as discussed herein, for example, L may represent a bond or a bivalent substituent group, and wherein X represents an optionally substituted hydrocarbon group, for example a monoacid or diacid lipid, or a salt thereof. In some embodiments, the bivalent substituent group comprises: an alkylene group, a carbonyl group, an oxycarbonyl group, an imino group, an alkylimino group, a sulfonyl group, an oxy group, a sulfide group, an ester bond, an amide bond, a carbonate bond or combinations thereof.

[0339] In some embodiments, L represents a bond or a bivalent substituent group, and Xrepresents an optionally substituted hydrocarbon group, or a salt thereof. For example, an illustrative GIP receptor agonist peptide has a Lys(R) residue, wherein the (R) portion of the Lys(R) residue is represented as X-L-, wherein X is a bivalent substituent group comprising an alkylene group, a carbonyl group, an oxycarbonyl group, an imino group, an alkylimino group, a sulfonyl group, an oxy group, a sulfide group, an ester bond, an amide bond, a carbonate bond or combinations thereof

[0340] In some embodiments, an illustrative Lys(R) can include an (R) group defined asX-L- group, wherein the bivalent substituent X is a C17-C22monoacid, a C17-C22diacid or an acetyl 59057274.1group. Some exemplary X moieties may include: X represents C17-C22 linear saturated dicarboxylic acid.

[0341] In some embodiments, (R) represents X-L-, wherein L represents a bivalent linkercomprising PEG and / or amino acid or consisting of PEG and / or one or more amino acids, for example, a Gly2-10- linker, and X represents a substituent group. A known PEG linker, an amino acid linker or combinations thereof may be used as illustrative examples of a bivalent linker, as long as it is able to link Lys to a substituent group. Alternatively, in some embodiments, R represents X-L-, wherein L represents a bond or a bivalent substituent group, and X represents an optionally substituted hydrocarbon group, or a salt thereof. A known bivalent substituent group may include, but is not limited to, an alkylene group, a carbonyl group, an oxycarbonyl group, an imino group, an alkylimino group, a sulfonyl group, an oxy group, a sulfide group, an ester bond, an amide bond, a carbonate bond or combinations thereof may be used.

[0342] In some embodiments, L represents (PEG3)2-, Abu-, (Gly)(2-10)-, gGlu(1-3)-, orcombinations thereof. In some embodiments, L represents (PEG3)2-gGlu-. In some examples, L represents Abu-gGlu-. In other examples, L represents (Gly)5-gGlu-, or (Gly)6-gGlu-. In some embodiments, L represents a glycine peptide having from about two to about ten glycines linked, or from about two to about seven glycines linked. In some examples, L represents (Gly)5-6-, or 59057274.1(Gly)5-, GGGGG-, or GGGGG-gGlu-. In some examples, L represents 2OEGgEgE, OEGgEgE, 2OEGgE, 3OEGgEgE, G5gEgE, 2OEGgEgEgE, 2OEG, or G5gEgE.

[0343] In some embodiments, L represents (PEG3)2-. In some embodiments, L represents(Gly)2-10-, for example, (Gly)(5-6). In some further embodiments, L represents a combination of groups, such as one or more PEG molecules linked to a glycine peptide: Gly2-10 for example, L may be (PEG3)2-(Gly)5-6-, or (PEG3)2-(Gly)5-.

[0344] In some embodiments, the (R) group attached to an amino acid, for example, a Lysresidue represents X-L-, wherein L represents a bivalent linker comprising PEG and / or one or more amino acids or consisting of PEG and / or one or more amino acids, and X represents a substituent group. A known PEG linker, an amino acid linker or combinations thereof may be used as the bivalent linker as long as it is able to link, a Lys residue to a substituent group. Alternatively, R represents X-L-, wherein L represents a bond or a bivalent substituent group, and X represents an optionally substituted hydrocarbon group, or a salt thereof. A known bivalent substituent group including, but are not limited to, an alkylene group, a carbonyl group, an oxycarbonyl group, an imino group, an alkylimino group, a sulfonyl group, an oxy group, a sulfide group, an ester bond, an amide bond, a carbonate bond or combinations thereof may be used. In some embodiments, (R) represents X-L-, wherein L is one or a combination of more than one selected from: 59057274.1a glycine linker comprising one or two to nine-linked glycine(s) or a single bond, and X represents C17-C22monoacid or diacid, or an acetyl group. In some embodiments, a linker L, can be coupled or linked covalently to a side chain of at least one amino acid, or modified amino acid for example, a Lys residue of the GIP receptor agonist peptide being covalently attached to a substituent group. In an embodiment, the selective GIP receptor agonist peptide is covalently attached to an (R) group, wherein the (R) group is a hydrophilic polymer, and the Lys(R) residue is positioned at an amino acid position ranging from A14 to A30. In an embodiment, the selective GIP receptor 59057274.1agonist peptide is covalently attached to a hydrophilic polymer, for example, the hydrophilic polymer is a polyethylene glycol (PEG) molecule or a variant thereof.

[0345] In some embodiments, the linker L is a PEG molecule, for example, PEG3(n),PEG(2)(n), or mPEG having a weight average molecular weight of about 5 – 30 kDa. In some embodiments, L can be any combination of PEG3(n), PEG(2)(n), gGlu(n), D-gGlu(n), AMBZ(n), GABA(n), G(x), NpipAc(n), Tra(n), eLya(n), where n = 1 – 5 and x = 1 -10. Exemplary PEG linkers can be used as part of an (R) group in a substituted Lys residue, for example, located at one or more of A14-A30, for example, at an amino acid position: A14, A17, A18, A20, A21, A24, A29, or A30, wherein the mPEG linker can include one or more of the following additional mPEG linkers: InX to a Cys amino acid can include a mPEGmolecule having an average molecular weight of about 5 – 30 kDa. In some embodiments, illustrative PEG linkers for attachment to a Cys side chain can include: 59057274.1

[0346] , GGGG-(Teda:C14diacid), Teda-GGGGG-, Teda-GGGGGG-, Peda-GGGG-(Peda:C15diacid), Peda- GGGGG-, Peda-GGGGGG-, Heda-GGGG-( Heda:C16 diacid), Heda-GGGGG-, Heda- GGGGGG-, Heda-GGGGGGGGG-.

[0347] Alternatively, the (R) group represents X-L-, wherein L represents a glycine linkercomprising five or six-linked glycines, and X represents C14-C16 linear saturated dicarboxylic acid.

[0348] Alternatively, the (R) group represents X-L-, wherein L represents a bond or a bivalentsubstituent group, and X represents an a C14-C16fatty acid, or a C14-C16acylated fatty acid or a C14-C16dicarboxylic acid, or a salt thereof. In some embodiments, the X represents a palmitic fatty acid used to add a palmitoyl group to the epsilon amine side group of a Lys residue, for example, a Lys reside in the GIP receptor agonist peptide.

[0349] In other embodiments, the GIP receptor agonist peptide has one, or two modified lysineresidues, i.e. Lys(R), wherein the (R) group represents X-L-, wherein L represents a glycine linker comprising three, four, five or six-linked glycines, and X represents C14-C16linear saturated dicarboxylic acid. In an embodiment, the acyl group is a C14to C16fatty acyl group, for example 59057274.1a palmitoyl or myristoyl fatty acyl group.

[0350] In an embodiment, the GIP receptor agonist peptide is covalently attached to an (R)group, wherein the (R) group is a hydrophilic polymer at any amino acid position ranging from A14 to A30. In an embodiment, the GIP receptor agonist peptide is covalently attached to a hydrophilic polymer at amino acid position, A14, A17, A18, A20, A21, A24, A29, or A30, or combinations thereof, for example, at positions A14-A30 or from A14 to A21. For example, the hydrophilic polymer may be attached to the side chain of a Lys residue of the GIP receptor agonist peptide. In an embodiment, the hydrophilic polymer is a polyethylene glycol (PEG). The mPEG polymer may also be further conjugated to a glycine linker, i.e. (Gly)(2-8)-, or to one or more gGlu- residues, for example, gGlu(1-3)-. In some examples, the PEG has a weight average molecular weight of about 1,000 Daltons to about 60,000 Daltons, such as about 5,000 Daltons to about 40,000 Daltons, or about 1,000 Daltons, or 5,000 Daltons, or 10,000 Daltons, or 12,000 Daltons, or 14,000 Daltons to about 20,000 Daltons.

[0351] In some embodiments, methods for conjugating a polyethylene glycol (PEG) polymerto a reactive amine or sulfhydryl group is well known in the art. For example, PEG can be conjugated to a lysine amine sidechain using an amine-reactive pegylated crosslinker. A bis(succinimidyl)penta- (ethylene glycol) spacer arm can be used as a homobifunctional, amine- 59057274.1to-amine crosslinker that contain N-hydroxy-succinimide (NHS) esters at both ends of a PEG spacer arm. An amine-reactive crosslinker that contains a PEG spacer arm. A bis-succinimide ester- activated PEG compound may be used for crosslinking between primary amines (-NH2) in GIP receptor agonist peptides of the present disclosure. The N-hydroxysuccinimide ester (NHS) groups at either end of the PEG spacer react specifically and efficiently with lysine and N-terminal amino groups at pH 7-9 to form stable amide bonds. Other homobifunctional, sulfhydryl-reactive crosslinkers that contain the maleimide group at either end of a PEG spacer may be used to couple PEG to a Cys amino acid of a GIP receptor agonist peptide. Heterofunctional crosslinking spacer arms may also be used when two different reactive groups are used as the linkage groups, e.g. an amine group and a sulfhydryl group. A sulfhydryl-reactive crosslinker that contains a PEG spacer arm, may be used to couple a PEG polymer to a GIP receptor agonist peptide. In some embodiments, a bismaleimide-activated PEG compound may be used for crosslinking between sulfhydryl (-SH) groups in proteins and other thiol molecules. The maleimide groups at either end of the PEG spacer may react specifically and efficiently with reduced sulfhydryls at pH 6.5-7.5 to form stable thioether bonds. In other embodiments, direct coupling of a PEG molecule to a GIP receptor agonist peptide may be accomplished using known methods in the art. For example, a well known technique whereby a peptide may be covalently modified with PEG groups requiring 59057274.1PEG compounds that contain a reactive or targetable functional group at one end. The simplest method to pegylate peptides, which are rich in surface primary amines, is to use a PEG compound that contains an NHS ester group at one end, for example, a methyl-(PEG)n-NHS ester. In a similar fashion, methyl-(PEG)n-maleimide (wherein n can be from 20-300) may be used to couple a PEG molecule to a Cys containing peptide of the present disclosure. Methods known in the art for conjugation of polyethylene glycol polymers of various lengths ranging from 1,000 Daltons to 20,000 Daltons or more are provided in 1.Hermanson, G.T. (2013). 3rd Edition. Bioconjugate Techniques, Academic Press, Veronese, F. and Harris, J.M. Eds. (2002). Peptide and protein PEGylation. Advanced Drug Delivery Review 54(4), 453-609: Zalipsky, S., et al., “Use of Functionalized Poly(Ethylene Glycols) for Modification of Polypeptides” in Polyethylene Glycol Chemistry: Biotechnical and Biomedical Applications, J. M. Harris, Plenus Press, New York (1992); and in Zalipsky (1995) Advanced Drug Reviews 16:157-182 the disclosures of all of these references are hereby incorporated by reference herein in their entireties.

[0352] In various embodiments, the GIP receptor agonist peptide disclosed herein with thelipidated Lys(R) residues positioned between amino acids A14 and A30, for example, at amino acid positions A14, A17, A18, A20, A21, A24, A28, A29, or A30, provide GIPR agonist peptides having enhanced ½ life of elimination, % remaining after 48 hours in serum, and solubility in 59057274.1various media, when compared to GIPR agonist peptides in the art. In some embodiments, the position of the lipidated lysine residue, the sequence of the GIPR peptide and the length of the lipid used in the (R) substituent on the Lys residue play a role in the improved half-life and solubility of the GIPR peptide, that enables the GIPR agonist peptides to be dosed in a therapeutically effective way to a subject in need of antiemetic activity once per day (Q1D), for example, once per 24 hours. The enhanced ½ life of elimination, % remaining after 48 hours in serum, and solubility in various media are illustrated in the Examples section of the present disclosure.

[0353] In various embodiments, GIP receptor agonist peptides disclosed herein which aresuitable for Q1D, or once per day dosing to treat emesis, including nausea and / or vomiting, have a human intravenous (IV) half life of elimination in human serum, ranging between 3-12 hours, or 4-10 hours, or for example, ranging between 4-6 hours. In various embodiments, GIP receptor agonist peptides disclosed herein which are suitable for Q1D dosing, or once per day dosing or once per 24 hours dosing, to treat emesis, including nausea and / or vomiting, have a solubility of greater than 10 mg / mL, or greater than 15 mg / mL, or greater than 20mg / mL, or greater than 30 mg / mL, or greater than 40 mg / mL, or greater than 50 mg / mL, or greater than 60 mg / mL, or greater than 75 mg / mL, or greater than 100 mg / mL, or greater than 125 mg / mL (for example, when tested 59057274.1in a dissolution test using phosphate buffer at pH 7.4 ); and a human intravenous half life of elimination in human serum ranging between 3 to 24 hours, or for example, ranging between 3 to 12 hours, or from 4 to 10 hours, or from 4 to 6 hours, and all integers therebetween of the stated ranges. In various embodiments, GIP receptor agonist peptides disclosed herein which are suitable for Q1D dosing, or once per day dosing, or once per 24 hours dosing, to treat emesis, including nausea and / or vomiting, in a mammal, for example, a human, have a solubility of 15 mg / mL, or greater; and a human intravenous half life of elimination ranging between about 3-18 hours, or for example, ranging between 4 hours to about 10 hours. In various embodiments, the GIPR agonist peptides of the present disclosure have a human intravenous half life of elimination in humans ranging from 4 to 10 hours as determined with the methods of the Examples below, and a solubility greater than 15 mg / mL, or 20 mg / mL, or 25 mg / mL, for example, greater than 30 mg / mL, or greater than 40 mg / mL, or greater than 45 mg / ml, or greater than 50 mg / mL or higher at pH 7.4.

[0354] In various embodiments, GIP receptor agonist peptides disclosed herein which aresuitable for Q1D dosing, or once per day dosing, or once per 24 hours dosing, to treat emesis, including nausea and / or vomiting, in a mammal, for example, a human, have a solubility of 15- 100 mg / mL, or greater; and a human intravenous half life of elimination ranging from 3 hours to about 16 hours, for example, a human intravenous half life of elimination ranging from about 4 59057274.1hours to about 14 hours, or ranging from about 4 hours to 10 hours as determined with the methods of the Examples below, and an amino acid sequence length of 30-31 or 39 amino acids, a substituted (Lys(R)) Lysine residue positioned in the amino acid position of A14 or A21, a lipid characterized as a C14diacid and a linker selected from 2OEGgE, 2OEGgEgE, and GGGGG.

[0355] In various embodiments, GIP receptor agonist peptides disclosed herein which aresuitable for Q1D dosing, or once per day dosing, or once per 24 hours dosing, to treat emesis, including nausea and / or vomiting, in a mammal, for example, a human, have a solubility of 15- 100 mg / mL, or greater; and a human intravenous half life of elimination ranging from 3 hours to about 16 hours, for example, a human intravenous half life of elimination ranging from about 4 hours to about 14 hours, or ranging from about 4 hours to 10 hours as determined with the methods of the Examples below, and an amino acid sequence length of 30-31 or 39 amino acids, a substituted (Lys(R)) Lysine residue positioned in the amino acid position of A14 or A21, a lipid characterized as a C14 diacid and a linker selected from 2OEGgE, 2OEG2gE, 2OEGgEgE, and GGGGG. In various embodiments, GIP receptor agonist peptides disclosed herein which are suitable for Q1D dosing, or once per day dosing, or once per 24 hours dosing, to treat emesis, including nausea and / or vomiting, in a mammal, for example, a human, have a solubility of 15- 100 mg / mL, or greater; and a human intravenous half life of elimination ranging from 3 hours to 59057274.1about 16 hours, for example, a human intravenous half life of elimination ranging from about 4 hours to about 14 hours, or ranging from about 4 hours to 10 hours as determined with the methods of the Examples below, and an amino acid sequence length of 30-31 or 39 amino acids, a substituted (Lys(R)) Lysine residue positioned in the amino acid position of A21, a lipid characterized as a C14 diacid and a linker selected from 2OEGgE, 2OEG2gE, 2OEGgEgE, and GGGGG. In some embodiments, a substituted (Lys(R)) Lysine residue is positioned in the amino acid position of A21, but not A14. In some embodiments, the GIP receptor agonist peptides disclosed herein are suitable for once a week (QW) administration.

[0356] Solubility of the GIPR peptides may be determined by dissolution in a phosphatebuffer followed by quantitation using liquid chromatography, for example, High Performance Liquid Chromatography (HPLC). An illustrative method is provided. For determination of the solubility of the GIPr agonist peptides, 3 mg of peptides are weighted out in a small glass vial. 100µL of 200mM Phosphate buffer pH 7.4 are added and the vial is sonicated / vortexed as necessary for a maximum of 1 min. A visual inspection is performed, If the sample is fully dissolved, the solubility is recorded as 30mg / mL. If insoluble material is observed in the tube the addition of 100 µL of buffer and mixing is repeated until complete dissolution. If the peptide is not soluble in 500 µL of buffer, it is labeled as solubility < 6mg / mL. The solubility can be confirmed 59057274.1by RP-HPLC after filtration on 0.2μm filter on an Agilent 1200 system with a Kinetex column form Phenomenex® (2.6µm EVO C18100 Å, LC Column 50 x 3.0 mm) kept at 40⁰C, the eluent A is 0.05% TFA in Water, B is 0.035% TFA in Acetonitrile at a 0.6ml / min flow rate. The gradient was from 20 to 70 over 5 min, the column is then washed for 1min at 90% B. UV monitoring at 215nm was used to monitor peptide concentration. Standards may also be run on the same chromatographical experiment, to obtain standard measurements at 215 nm, from which a standard curve may be calculated and soluble peptide concentrations may be extrapolated from the standard curve.

[0357] In various embodiments, the GIP receptor agonist peptide disclosed herein, forexample, as used in the preparation of a medicament, a composition, or for use in the prevention and / or treatment of a condition, or disorder, or in a method of prevention and / or treatment as disclosed herein, as represented by a GIP receptor agonist peptide, or a pharmaceutically acceptable salt thereof, has an amino acid sequence as provided in any one of Formulae (I), (I-A) and / or (I-B).

[0358] In various embodiments, suitable GIPR agonist peptides having the appropriatepharmacokinetics and pharmacodynamics required for therapeutically effective treatment of a subject with emesis or displaying one or more symptoms of emesis, for example, nausea and / or 59057274.1vomiting or for use to prevent emesis by dosing Q1D, or once per day, for example, once per 24 hours, have the following amino acid sequence and lipid-linker characteristics: in accordance with Formulae (I), (I-A) and / or (I-B).

[0359] In some embodiments, the GIP receptor agonist peptide is of Formula (I):P1-Tyr-Aib-Glu-Gly-Thr-A6-A7-Ser-A9-Tyr-A11-Ile-A13-A14-A15-A16-A17-A18-Gln-A20- A21-Phe-Val-A24-A25-A26-A27-A28-A29-A30-A31-A32-A33-A34-A35-A36-A37-A38-A39- A40-P2(SEQ ID NO: 13), or a pharmaceutically acceptable salt thereof; wherein P1is: H or methyl; P2is: -NH2or -OH; A6 is: Ala, Leu, Phe, Thr, or Val; A7 is: Ile or Val; A9 is: any amino acid other than Glu or Asp; A11 is: Ser or Phe; A13 is: Aib or Ala; A14 is: Leu, Nle, Met, or Lys(R); A15 is: Asp or Glu; 59057274.1A16 is: Arg or Lys; A17 is: Leu, Glu, Gln, Aib, Ile, or Lys(R); A18 is: Ala, His, or Lys(R); A20 is: Aib, Lys, or Lys(R); A21 is: Glu, Asn, Asp, Lys, Gln, or Lys(R); A24 is: Glu, Asn, Gln, Lys, or Lys(R); A25 is: Ser, Tyr, Trp, or Lys(R); A26 is: Leu or Iva; A27 is: Leu or Ala; A28 is: Ala or Lys; A29 is: Gly, Gln, or Lys(R); A30 is: Glu, Gly, Arg, Lys, or Lys(R); A31 is: Pro or Gly; A32 is: Ser or a deletion; A33 is: Ser or a deletion; A34 is: Gly or a deletion; A35 is: Ala or a deletion; 59057274.1A36 is: Pro or a deletion; A37 is: Pro or a deletion; A38 is: Pro or a deletion; A39 is: Ser or a deletion; and A40 is: Lys, Arg, or a deletion.

[0360] In some embodiments, at least one of A14, A17, A18, A20, A21, A24, A25, A29, orA30 is Lys(R). In certain embodiments, in the residue Lys(R), the (R) portion represents -L-X, wherein L represents a linker and is selected from the group consisting of 1OEGgE, 2OEG, 2OEGgE, 2OEGgEgE, 2OEGgEgEgE, 3OEGgE, 3OEGgEgE, G3gEgE, G4gE, G4gEgE, GGGGG, G5gE, G5gEgE, OEGgEgE, and OEGgEgEgE; and X represents C17-C22monoacid or C17-C22diacid.

[0361] In some embodiments, the GIP receptor agonist peptide according to Formula (I) hasan amino acid sequence of Formula (I), wherein P1is H. In some embodiments, P1is methyl.

[0362] In some embodiments, the GIP receptor agonist peptide according to Formula (I) hasan amino acid sequence of Formula (I), wherein P2is -NH2. In some embodiments, P2is -OH.

[0363] In various embodiments, the GIP receptor agonist peptide of Formula (I) includes apeptide wherein P1is methyl, (Me), and P2is –OH. In some embodiments, the GIP receptor agonist 59057274.1peptide of Formula (I) includes a peptide wherein P1is H, and P2is –NH2.

[0364] In some embodiments, the GIP receptor agonist peptide according to Formula (I) or thepharmaceutically acceptable salt thereof, has an amino acid sequence of Formula (I), wherein A6 is Val.

[0365] In some embodiments, the GIP receptor agonist peptide according to Formula (I) or thepharmaceutically acceptable salt thereof, has an amino acid sequence of Formula (I), wherein A9 is any amino acid other than Glu or Asp, for example, A9 is: Ala, Arg, Asn, Cys, Gln, Gly, His, Ile, Leu, Lys, Met, Phe, Pro, Ser, Thr, Trp, Tyr, or Val. In some embodiments, the GIP receptor agonist peptide according to Formula (I) or the pharmaceutically acceptable salt thereof, has an amino acid sequence of Formula (I), wherein A9 is: Ala, Arg, Asn, Cys, Gln, Gly, His, Ile, Leu, Lys, Met, Phe, Pro, Ser, Thr, Trp, Tyr, or Val. In some embodiments, the GIP receptor agonist peptide according to Formula (I) or the pharmaceutically acceptable salt thereof, has an amino acid sequence of Formula (I), wherein A9 is Leu.

[0366] In some embodiments, the GIP receptor agonist peptide according to Formula (I) or thepharmaceutically acceptable salt thereof, has an amino acid sequence of Formula (I), wherein A15 as Asp.

[0367] In some embodiments, the GIP receptor agonist peptide according to Formula (I) or the59057274.1pharmaceutically acceptable salt thereof, has an amino acid sequence of Formula (I), wherein A25 is Trp.

[0368] In some embodiments, the GIP receptor agonist peptide according to Formula (I) or thepharmaceutically acceptable salt thereof, has an amino acid sequence of Formula (I), wherein A29 is: Gly, Gln, or Lys(R).

[0369] In some embodiments, the GIP receptor agonist peptide according to Formula (I) or thepharmaceutically acceptable salt thereof, has an amino acid sequence of Formula (I), wherein A30 is Gly, Arg, Lys, or Lys(R).

[0370] In some embodiments, the GIP receptor agonist peptide according to Formula (I) or thepharmaceutically acceptable salt thereof, has an amino acid sequence of Formula (I), wherein A11 is Ser.

[0371] In some embodiments, the GIP receptor agonist peptide according to Formula (I) or thepharmaceutically acceptable salt thereof, has an amino acid sequence of Formula (I), wherein A13 is Aib.

[0372] In some embodiments, the GIP receptor agonist peptide according to Formula (I) or thepharmaceutically acceptable salt thereof, has an amino acid sequence of Formula (I), wherein A14 is Leu. 59057274.1

[0373] In some embodiments, the GIP receptor agonist peptide according to Formula (I) or thepharmaceutically acceptable salt thereof, has an amino acid sequence of Formula (I), wherein A14 is Lys(R).

[0374] In some embodiments, the GIP receptor agonist peptide according to Formula (I) or thepharmaceutically acceptable salt thereof, has an amino acid sequence of Formula (I), wherein A16 is Arg.

[0375] In some embodiments, the GIP receptor agonist peptide according to Formula (I) or thepharmaceutically acceptable salt thereof, has an amino acid sequence of Formula (I), wherein A17 is Glu, Aib, Gln, or Lys(R).

[0376] In some embodiments, the GIP receptor agonist peptide according to Formula (I) or thepharmaceutically acceptable salt thereof, has an amino acid sequence of Formula (I), wherein A17 is Glu or Aib.

[0377] In some embodiments, the GIP receptor agonist peptide according to Formula (I) or thepharmaceutically acceptable salt thereof, has an amino acid sequence of Formula (I), wherein A17 is Glu.

[0378] In some embodiments, the GIP receptor agonist peptide according to Formula (I) or thepharmaceutically acceptable salt thereof, has an amino acid sequence of Formula (I), wherein A17 59057274.1is Lys(R).

[0379] In some embodiments, the GIP receptor agonist peptide according to Formula (I) or thepharmaceutically acceptable salt thereof, has an amino acid sequence of Formula (I), wherein A18 is Ala.

[0380] In some embodiments, the GIP receptor agonist peptide according to Formula (I) or thepharmaceutically acceptable salt thereof, has an amino acid sequence of Formula (I), wherein A20 is Aib.

[0381] In some embodiments, the GIP receptor agonist peptide according to Formula (I) or thepharmaceutically acceptable salt thereof, has an amino acid sequence of Formula (I), wherein A21 is Lys(R).

[0382] In some embodiments, the GIP receptor agonist peptide according to Formula (I) or thepharmaceutically acceptable salt thereof, has an amino acid sequence of Formula (I), wherein A24 is Glu, Asn, or Gln.

[0383] In some embodiments, the GIP receptor agonist peptide according to Formula (I) orthe pharmaceutically acceptable salt thereof, has an amino acid sequence of Formula (I), wherein A24 is Asn.

[0384] In some embodiments, the GIP receptor agonist peptide according to Formula (I) or59057274.1the pharmaceutically acceptable salt thereof, has an amino acid sequence of Formula (I), wherein A24 is Lys(R).

[0385] In some embodiments, the GIP receptor agonist peptide according to Formula (I) orthe pharmaceutically acceptable salt thereof, has an amino acid sequence of Formula (I), wherein A26 is Leu.

[0386] In some embodiments, the GIP receptor agonist peptide according to Formula (I) orthe pharmaceutically acceptable salt thereof, has an amino acid sequence of Formula (I), wherein A28 is Ala.

[0387] In some embodiments, the GIP receptor agonist peptide according to Formula (I) orthe pharmaceutically acceptable salt thereof, has an amino acid sequence of Formula (I), wherein A29 is Gly or Gln.

[0388] In some embodiments, the GIP receptor agonist peptide according to Formula (I) orthe pharmaceutically acceptable salt thereof, has an amino acid sequence of Formula (I), wherein A29 is Gln.

[0389] In some embodiments, the GIP receptor agonist peptide according to Formula (I) orthe pharmaceutically acceptable salt thereof, has an amino acid sequence of Formula (I), wherein A30 is Gly or Arg. 59057274.1

[0390] In some embodiments, the GIP receptor agonist peptide according to Formula (I) orthe pharmaceutically acceptable salt thereof, has an amino acid sequence of Formula (I), wherein A30 is Gly.

[0391] In some embodiments, the GIP receptor agonist peptide according to Formula (I) orthe pharmaceutically acceptable salt thereof, has an amino acid sequence of Formula (I), wherein A30 is Arg.

[0392] In some embodiments, the GIP receptor agonist peptide according to Formula (I)or the pharmaceutically acceptable salt thereof, has an amino acid sequence of Formula (I), wherein A40 is a deletion.

[0393] In some embodiments, the GIP receptor agonist peptide according to Formula (I) orthe pharmaceutically acceptable salt thereof, has an amino acid sequence of Formula (I), wherein the (R) portion of Lys(R) represents -L-X, wherein L represents a linker and is selected from the group consisting 2OEGgE, 2OEGgEgE, and GGGGG. In some embodiments, L is 2OEGgE. In further embodiments, L is GGGGG.

[0394] In some embodiments, the GIP receptor agonist peptide according to Formula (I) orthe pharmaceutically acceptable salt thereof, has an amino acid sequence of Formula (I), wherein the (R) portion of Lys(R) represents -L-X, wherein L represents a linker and is 2OEGgE. 59057274.1

[0395] In some embodiments, the GIP receptor agonist peptide according to Formula (I) orthe pharmaceutically acceptable salt thereof, has an amino acid sequence of Formula (I), wherein the (R) portion of Lys(R) represents -L-X, wherein X represents a C17-C22monoacid. In some embodiments, X represents a C17-C22diacid, for example, a C17diacid, a C18diacid, or a C19diacid. In some embodiments, the GIP receptor agonist peptide according to Formula (I) or the pharmaceutically acceptable salt thereof, has an amino acid sequence of Formula (I), wherein the (R) portion of Lys(R) represents -L-X, wherein X represents a C14 diacid.

[0396] In some embodiments, the GIP receptor agonist peptide according to Formula (I) orthe pharmaceutically acceptable salt thereof, has an amino acid sequence of Formula (I), wherein A21 is Lys(R); wherein the (R) portion of Lys(R) represents -L-X, and L is selected from the group consisting of 2OEGgE and 2OEG2gE; and X represents C14-C16diacid.

[0397] In some embodiments, the GIP receptor agonist peptide according to Formula (I) orthe pharmaceutically acceptable salt thereof, has an amino acid sequence of Formula (I), wherein A21 is Lys(R); wherein the (R) portion of Lys(R) represents -L-X, and L is 2OEGgE; and X represents a C14 diacid.

[0398] In some embodiments, the GIP receptor agonist peptide according to Formula (I) orthe pharmaceutically acceptable salt thereof, has an amino acid sequence of Formula (I), wherein 59057274.1A30-A31-A32-A33-A34-A35-A36-A37-A38-A39 is Arg-Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser.

[0399] In some embodiments, the GIP receptor agonist peptide according to Formula (I) orthe pharmaceutically acceptable salt thereof, has an amino acid sequence of Formula (I), wherein, A7 is: Ile or Val A11 is: Ser or Phe; A13 is: Aib or Ala; A14 is: Leu, Nle, Met, or Lys(R); A16 is: Arg or Lys; A17 is: Leu, Gln, Aib, Ile, or Lys(R); A18 is: Ala or His A21 is: Glu, Asn, Asp, Lys, Gln, or Lys(R); A24 is: Glu, Asn, Gln, or Lys(R); A26 is: Leu or Iva; A27 is: Leu or Ala; A28 is: Ala or Lys; A29 is Gly, Gln, or Lys; 59057274.1A30 is Gly, Arg, Lys, or Lys(R); A31 is: Pro or Gly; and A40 is: Lys, Arg, or a deletion; and wherein in the residue Lys(R), the (R) portion represents -L-X, wherein L represents a linker and is selected from the group consisting of 2OEGgE, 2OEG2gE, and GGGGG; and X represents a C17-C22 monoacid or a C17-C22 diacid. In some embodiments, the residue Lys(R), the (R) portion represents -L-X, wherein L represents a linker and is 2OEGgE; and X represents a C14-C16 diacid. In some embodiments, the residue Lys(R), the (R) portion represents -L-X, wherein L represents a linker and is 2OEGgE; and X represents a C14diacid.

[0400] In some embodiments, the the GIP receptor agonist peptide according to Formula (I)or the pharmaceutically acceptable salt thereof, has an amino acid sequence represented by Formula (I-A): P1-Tyr-Aib-Glu-Gly-Thr-Val-A7-Ser-Leu-Tyr-A11-Ile-A13-A14-Asp-A16-A17-A18-Gln-A20- A21-Phe-Val-A24-Trp-A26-A27-A28-A29-A30-A31-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser-A40-P2(SEQ ID NO: 14), or a pharmaceutically acceptable salt thereof; wherein P1is: H or methyl; 59057274.1P2is: -NH2 or -OH; A7 is: Ile or Val; A11 is: Ser or Phe; A13 is: Aib or Ala; A14 is: Leu, Nle, Met, or Lys(R); A16 is: Arg or Lys; A17 is: Leu, Glu, Gln, Aib, Ile, or Lys(R); A18 is: Ala, His, or Lys(R); A20 is: Aib, Lys, or Lys(R); A21 is: Glu, Asn, Asp, Lys, Gln, or Lys(R); A24 is: Glu, Asn, Gln, Lys, or Lys(R); A26 is: Leu or Iva; A27 is: Leu or Ala; A28 is: Ala or Lys; A29 is: Gly, Gln, or Lys(R); A30 is: Gly, Arg, Lys, or Lys(R); A31 is: Pro or Gly; 59057274.1A40 is: Lys, Arg, or a deletion; wherein at least one of A14, A17, A18, A20, A21, A24, A25, A29, or A30 is Lys(R); and wherein in the residue Lys(R), the (R) portion represents -L-X, wherein L represents a linker and is selected from the group consisting of 1OEGgE, 2OEG, 2OEGgE, 2OEGgEgE, 2OEGgEgEgE, 3OEGgE, 3OEGgEgE, G3gEgE, G4gE, G4gEgE, GGGGG, G5gE, G5gEgE, OEGgEgE, and OEGgEgEgE; and X represents C17-C22 monoacid or C17-C22 diacid.

[0401] In some embodiments, the GIP receptor agonist peptide according to Formula (I) orthe pharmaceutically acceptable salt thereof, has an amino acid sequence represented by Formula (I-B): P1-Tyr-Aib-Glu-Gly-Thr-Val-Val-Ser-Leu-Tyr-Ser-Ile-Aib-Leu-Asp-A16-Glu-A18-Gln-A20- A21-Phe-Val-Asn-Trp-A26-A27-A28-A29-A30-Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser-A40-P2, or a pharmaceutically acceptable salt thereof; wherein A21 is Lys(R); and A40 is: a deletion; 59057274.1wherein in the residue Lys(R), the (R) portion represents -L-X, wherein L represents a linker and is selected from the group consisting of 2OEGgE, 2OEGgEgE, and GGGGG; and X represents a C17-C22monoacid or a C17-C22diacid and A40 is a deletion.

[0402] In some embodiments, the GIP receptor agonist peptide according to Formula (I) orthe pharmaceutically acceptable salt thereof, has an amino acid sequence: H-Tyr-Aib-Glu-Gly-Thr-Val-Val-Ser-Leu-Tyr-Ser-Ile-Aib-Lys(R)-Asp-Arg-Glu-Ala-Gln-Aib- Glu-Phe-Val-Asn-Trp-Leu-Leu-Ala-Gln-Arg-Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser-NH2; and Lys(R) is 2OEGgE-C15 diacid.

[0403] In some embodiments, the GIP receptor agonist peptide according to Formula (I) orthe pharmaceutically acceptable salt thereof, has an amino acid sequence: H-Tyr-Aib-Glu-Gly-Thr-Val-Val-Ser-Leu-Tyr-Ser-Ile-Aib-Leu-Asp-Arg-Glu-Ala-Gln-Aib- Lys(R)-Phe-Val-Asn-Trp-Leu-Leu-Ala-Gln-Arg-Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser-NH2; and Lys(R) is 2OEGgE-C14 diacid.

[0404] In some embodiments, the GIP receptor agonist peptide according to Formula (I) orthe pharmaceutically acceptable salt thereof, has an amino acid sequence: 59057274.1H-Tyr-Aib-Glu-Gly-Thr-Val-Val-Ser-Leu-Tyr-Ser-Ile-Aib-Leu-Asp-Arg-Glu-Ala-Gln-Aib- Lys(R)-Phe-Val-Asn-Trp-Leu-Leu-Ala-Gln-Arg-Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser-NH2; and Lys(R) is 2OEGgE-C18monoacid.

[0405] In some embodiments, the GIP receptor agonist peptide according to Formula (I) orthe pharmaceutically acceptable salt thereof, has an amino acid sequence: H-Tyr-Aib-Glu-Gly-Thr-Val-Val-Ser-Leu-Tyr-Ser-Ile-Aib-Leu-Asp-Arg-Glu-Ala-Gln-Aib- Lys(R)-Phe-Val-Glu-Trp-Leu-Leu-Ala-Gln-Arg-Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser-NH2; and Lys(R) is 2OEGgE-C14 diacid.

[0406] In some embodiments, the GIP receptor agonist peptide according to Formula (I) orthe pharmaceutically acceptable salt thereof, has at least three unnatural amino acids, for example, 3, or 4, or 5, or 6, or 7 unnatural amino acids, selected from: Aib-alpha- aminoisobutyric acid; mono-halo Phe - mono-halo phenylalanine; bis-halo Phe - bis-halo phenylalanine; mono-halo Tyr – mono-halo tyrosine; bis-halo Tyr – bis-halo Tyrosine; (D)-Tyr - D-tyrosine; (D)-Ala - D-Alanine; DesNH2-Tyr - desaminotyrosine; (D)-Phe - D-phenylalanine; esNH2-Phe- desaminophenylalanine; (D)-Trp - D-tryptophan; (D)3Pya - D-3-pyridylalanine; 2- Cl-(D)Phe - D-2-chlorophenylalanine; 3-Cl-(D)Phe - D-3-chlorophenylalanine; 4-Cl-(D)Phe - D- 4- chlorophenylalanine; 2-F-(D)Phe - D-2-fluorophenylalanine; 3-F(D)Phe - D-3- 59057274.1fluorophenylalanine; 3,5-DiF-(D)Phe - D-3,5-difluorophenylalanine; 3,4,5-TriF-(D)Phe - D- 3,4,5-trifluorophenylalanine; or D-Iva – D-Isovaline. In various embodiments, the GIP receptor agonist peptide has three unnatural amino acids. In various embodiments, the GIP receptor agonist peptide, or the pharmaceutically acceptable salt thereof, has three unnatural amino acids, and each of the three unnatural amino acids are each the unnatural amino acid Aib.

[0407] In various embodiments, exemplary GIP receptor agonist peptides having a structureas defined in any one of Formulae (I), (I-A) and / or (I-B) are described herein.

[0408] B. SYNTHESIS OF GIPR AGONIST PEPTIDES

[0409] The GIP receptor agonist peptide may be synthesized according to a peptide synthesismethod known in the art. The peptide synthesis method may be any of, for example, a solid phase synthesis process and a liquid phase synthesis process. That is, the object GIP receptor agonist peptide can be produced by repeating condensation of a partial peptide or amino acid capable of constituting the GIP receptor agonist peptide, and the remaining portion (which may be constituted by two or more amino acids) according to a desired sequence. When a product having the desirable sequence has a protecting group, the object GIP receptor agonist peptide can be produced by eliminating a protecting group. Examples of the condensing method and eliminating method of a protecting group to be known include methods described in the following (1)-(5). 59057274.1(1) M. Bodanszky and M.A. Ondetti: Peptide synthesis, Interscience Publishers, New York (1966) (2) Schroeder and Luebke: The Peptide, Academic Press, New York (1965) (3) Nobuo Izumiya, et al.: Peptide Gosei-no-Kiso to Jikken (Basics and experiments of peptide synthesis), published by Maruzen Co. (1975) (4) Haruaki Yajima and Shunpei Sakakibara: Seikagaku Jikken Koza (Biochemical Experiment) 1, Tanpakushitsu no Kagaku (Chemistry of Proteins) IV, 205 (1977) (5) Haruaki Yajima, ed.: Zoku Iyakuhin no Kaihatsu (A sequel to Development of Pharmaceuticals), Vol.14, peptide synthesis, published by Hirokawa Shoten.

[0410] After the reaction, the GIP receptor agonist peptide can be purified and isolated usingconventional methods of purification, such as solvent extraction, distillation, column chromatography, liquid chromatography, recrystallization, etc., in combination thereof. When the peptide obtained by the above-mentioned method is in a free form, it can be converted to a suitable salt by a known method; conversely, when the peptide is obtained in the form of a salt, the salt can be converted to a free form or other salt by a known method.

[0411] The starting compound may also be a salt. Examples of such salt include thoseexemplified as salts of the exemplified selective GIPr agonists mentioned below. 59057274.1

[0412] For condensation of protected amino acid or peptide, various activation reagentsusable for peptide synthesis can be used, which include trisphosphonium salts, tetramethyluronium salts, carbodiimides and the like. Examples of the trisphosphonium salt include benzotriazol-1-yloxytris(pyrrolizino)phosphoniumhexafluorophosphate (PyBOP), bromotris(pyrrolizino)phosphoniumhexafluorophosphate (PyBroP), 7-azabenzotriazol-1- yloxytris(pyrrolizino)phosphoniumhexafluorophosphate (PyAOP), examples of the tetramethyluronium salt include 2-(1H-benzotriazol-1-yl)-1,1,3,3- tetramethyluroniumhexafluorophosphate (HBTU), 2-(7-azabenzotriazol-1-yl)-1,1,3,3- tetramethyluroniumhexafluorophosphate (HATU), 2-(1H-benzotriazol-1-yl)-1,1,3,3- tetramethyluroniumtetrafluoroborate (TBTU), 2-(5-norbornane-2,3-dicarboxyimide)-1,1,3,3- tetramethyluroniumtetrafluoroborate (TNTU), O-(N-succimidyl)-1,1,3,3- tetramethyluroniumtetrafluoroborate (TSTU), and examples of the carbodiimide include N,N’- Dicyclohexylcarbodiimide (DCC), N,N’-diisopropylcarbodiimide (DIPCDI), N-ethyl-N’-(3- dimethylaminopropyl)carbodiimide hydrochloride (EDCI・HCl) and the like. For condensation using these, addition of a racemization inhibitor [e.g., N-hydroxy-5-norbornene-2,3-dicarboxylic imide (HONB), 1-hydroxybenzotriazole (HOBt), 1-Hydroxy-7-azabenzotriazole (HOAt), 3,4- Dihydro-3-hydroxy-4-oxo-1,2,3-benzotriazine (HOOBt), ethyl 2-cyano-2-(hydroxyimino)acetate 59057274.1(Oxyma)etc.] is example. A solvent to be used for the condensation can be appropriately selected from those known to be usable for peptide condensation reaction. For example, acid amides such as anhydrous or water-containing N,N-dimethylformamide, N,N-dimethylacetamide, N- methylpyrrolidone and the like, halogenated hydrocarbons such as methylene chloride, chloroform and the like, alcohols such as trifluoroethanol, phenol and the like, sulfoxides such as dimethylsulfoxide and the like, tertiary amines such as pyridine and the like, ethers such as dioxane, tetrahydrofuran and the like, nitriles such as acetonitrile, propionitrile and the like, esters such as methyl acetate, ethyl acetate and the like, an appropriate mixture of these and the like can be used. Reaction temperature is appropriately selected from the range known to be usable for peptide binding reactions, and is normally selected from the range of about -20°C to 90°C. An activated amino acid derivative is normally used from 1.5 to 6 times in excess. In solid phase synthesis, when a test using the ninhydrin reaction reveals that the condensation is insufficient, sufficient condensation can be conducted by repeating the condensation reaction without elimination of protecting groups. If the condensation is yet insufficient even after repeating the reaction, unreacted amino acids can be acylated with acetic anhydride, acetylimidazole or the like so that an influence on the subsequent reactions can be avoided.

[0413] Examples of the protecting groups for the amino groups of the starting amino acid59057274.1include benzyloxycarbonyl (Z), tert-butoxycarbonyl (Boc), tert-pentyloxycarbonyl, isobornyloxycarbonyl, 4-methoxybenzyloxycarbonyl, 2-chlorobenzyloxycarbonyl (Cl-Z), 2- bromobenzyloxycarbonyl (Br-Z), adamantyloxycarbonyl, trifluoroacetyl, phthaloyl, formyl, 2- nitrophenylsulphenyl, diphenylphosphinothioyl, 9-fluorenylmethyloxycarbonyl (Fmoc), trityl and the like.

[0414] Examples of the carboxyl-protecting group for the starting amino acid include aryl, 2-adamantyl, 4-nitrobenzyl, 4-methoxybenzyl, 4-chlorobenzyl, phenacyl and benzyloxycarbonylhydrazide, tert-butoxycarbonylhydrazide, tritylhydrazide and the like, in addition to the above-mentioned C1-6alkyl group, C3-10cycloalkyl group, or C7-14aralkyl group.

[0415] The hydroxyl group of serine or threonine can be protected, for example, byesterification or etherification. Examples of the group suitable for the esterification include lower (C2-4) alkanoyl groups such as an acetyl group and the like, aroyl groups such as a benzoyl group and the like, and the like, and a group derived from an organic acid and the like. In addition, examples of the group suitable for etherification include benzyl, tetrahydropyranyl, tert- butyl(But), trityl (Trt) and the like.

[0416] Examples of the protecting group for the phenolic hydroxyl group of tyrosine includeBzl, 2,6-dichlorobenzyl, 2-nitrobenzyl, Br-Z, tert-butyl and the like. 59057274.1

[0417] Examples of the protecting group for the imidazole of histidine include p-toluenesulfonyl (Tos), 4-methoxy-2,3,6-trimethylbenzenesulfonyl (Mtr), dinitrophenyl (DNP), benzyloxymethyl (Bom), tert-butoxymethyl (Bum), Boc, Trt, Fmoc and the like.

[0418] Examples of the protecting group for the guanidino group of arginine include Tos, Z,4-methoxy-2,3,6-trimethylbenzenesulfonyl (Mtr), p-methoxybenzenesulfonyl (MBS), 2,2,5,7,8- pentamethylchromane-6-sulfonyl (Pmc), mesitylene-2-sulfonyl (Mts), 2,2,4,6,7- pentamethyldihydrobenzofuran-5-sulfonyl (Pbf), Boc, Z, NO2 and the like.

[0419] Examples of the protecting group for a side chain amino group of lysine include Z,Cl-Z, trifluoroacetyl, Boc, Fmoc, Trt, Mtr, 4,4-dimethyl-2,6-dioxocyclohexylideneyl (Dde) and the like.

[0420] Examples of the protecting group for indolyl of tryptophan include formyl (For), Z,Boc, Mts, Mtr and the like.

[0421] Examples of the protecting group for asparagine and glutamine include Trt, xanthyl(Xan), 4,4’-dimethoxybenzhydryl (Mbh), 2,4,6-trimethoxybenzyl (Tmob) and the like.

[0422] Examples of activated carboxyl groups in the starting material include correspondingacid anhydride, azide, active esters [ester with alcohol (e.g., pentachlorophenol, 2,4,5- trichlorophenol, 2,4-dinitrophenol, cyanomethylalcohol, paranitrophenol, HONB, N- 59057274.1hydroxysuccimide, 1-hydroxybenzotriazole (HOBt), 1-hydroxy-7-azabenzotriazole(HOAt))] and the like. Examples of the activated amino group in the starting material include corresponding phosphorous amide.

[0423] Examples of the method for removing (eliminating) a protecting group include acatalytic reduction in a hydrogen stream in the presence of a catalyst such as Pd-black or Pd- carbon; an acid treatment using anhydrous hydrogen fluoride, methanesulfonic acid, trifluoromethanesulfonic acid, trifluoroacetic acid (TFA), trimethylsilyl bromide (TMSBr), trimethylsilyl trifluoromethanesulfonate, tetrafluoroboric acid, tris(trifluoro)boric acid, boron tribromide, or a mixture solution thereof; a base treatment using diisopropylethylamine, triethylamine, piperidine, piperazine or the like; and reduction with sodium in liquid ammonia, and the like. The elimination reaction by the above-described acid treatment is generally carried out at a temperature of -20°C to 40°C; the acid treatment is efficiently conducted by adding a cation scavenger such as anisole, phenol, thioanisole, metacresol and paracresol; dimethylsulfide, 1,4-butanedithiol, 1,2-ethanedithiol, triisopropylsilane and the like. Also, a 2,4-dinitrophenyl group used as a protecting group of the imidazole of histidine is removed by thiophenol treatment; a formyl group used as a protecting group of the indole of tryptophan is removed by deprotection by acid treatment in the presence of 1,2-ethanedithiol, 1,4-butanedithiol, or the like, 59057274.1as well as by alkali treatment with dilute sodium hydroxide, dilute ammonia, or the like.

[0424] Protection of a functional group that should not be involved in the reaction of astarting material and a protecting group, elimination of the protecting group, activation of a functional group involved in the reaction and the like can be appropriately selected from known protecting groups and known means.

[0425] In a method of preparing an amide of the peptide, a solid phase synthesis using a resinis used for amide synthesis, or the α-carboxyl group of the carboxy terminal amino acid is amidated, and a peptide chain is elongated to a desired chain length toward the amino group side. Thereafter, a peptide wherein the protecting group for the N-terminal α-amino group of the peptide chain only is removed and a peptide wherein the protecting group for the C-terminal carboxyl group only is removed of the peptide chain are prepared, and both peptides are condensed in a mixed solvent described above. For details about the condensation reaction, the same as above applies. After the protected peptide obtained by the condensation is purified, all protecting groups can be removed by the above-described method to yield a desired crude polypeptide. By purifying this crude peptide using various publicly known means of purification, and freeze-drying the main fraction, a desired amide of the peptide can be prepared.

[0426] When the GIP receptor agonist peptide is present as a configurational isomer such as59057274.1enantiomer, diastereomer etc., a conformer or the like, they are also encompassed within the description of a GIP receptor agonist peptide and each can be isolated by a means known per se or the above separation and purification methods on demand. In addition, when the GIP receptor agonist peptide is in the form of a racemate, it can be separated into S- and R-forms by conventional optical resolution.

[0427] When a GIP receptor agonist peptide includes stereoisomers, both the isomers aloneand mixtures of each isomers are also encompassed within the meaning of a GIP receptor agonist peptide. A GIP receptor agonist peptide can be chemically modified according to a method known per se and using substituent and polyethylene glycol. For example, a chemically modified GIP receptor agonist peptide can be produced by introducing substituent and / or conjugatedly binding polyethylene glycol to Cys residue, Asp residue, Glu residue, Lys residue and the like of a GIP receptor agonist peptide. Additionally, there may be a linker structure between the amino acid of the GIP receptor agonist peptide and substituent and polyethylene glycol.

[0428] A GIP receptor agonist peptide modified by a substituent and / or polyethylene glycol(PEG) produces for example, one or more effects related to promoting the biological activity, prolonging the blood circulation time, resistance to elimination, reducing the immunogenicity, enhancing the solubility, and enhancing the resistance to metabolism, of a therapeutically and 59057274.1diagnostically important peptide.

[0429] The molecular weight of PEG is not particularly limited and is normally about 1 K toabout 1000 K Daltons, or about 10 K to about 100 K Daltons, or about 20 K to about 60 K Daltons.

[0430] Modifying a selective GIPr agonist of the present disclosure by adding an (R)substituent can be conducted by introducing the (R) substituent based on known oxidation reaction and reduction reactions.

[0431] A method well known in the art can be used as a method for modifying a GIP receptoragonist peptide by PEG, and, for example, in addition to the exemplary methods listed above, the methods described below can be used. (1) A PEGylating reagent having an active ester (e.g., SUNBRIGHT MEGC-30TS (trade name), NOF Corp.) is bound to an amino group of the GIP receptor agonist peptide. (2) A PEGylating reagent having an aldehyde (e.g., SUNBRIGHT ME-300AL (trade name), NOF Corp.) is bound to the amino group of the GIP receptor agonist peptide. (3) A divalent cross-linking reagent (e.g., GMBS (Dojindo Laboratories), EMCS (Dojindo Laboratories), KMUS (Dojindo Laboratories), SMCC (Pierce)) is bound to an amino acid, (for example, a Lys and / or a Cys), of the GIP receptor agonist peptide , to 59057274.1which a PEGylating reagent having a thiol group (e.g., SUNBRIGHT ME-300-SH (trade name), NOF Corp.) is then bound. (4) A thiol group is introduced to a GIP receptor agonist peptide through an SH- introducing agent (e.g., D-cysteine residue, L-cysteine residue, Traut’s reagent), and this thiol group is reacted with a PEGylating reagent having a maleimide group (e.g., SUNBRIGHT ME-300MA (trade name), NOF Corp.). (5) A thiol group is introduced to GIP receptor agonist peptide through an SH- introducing agent (e.g., D-cysteine residue, L-cysteine residue, Traut’s reagent), and this thiol group is reacted with a PEGylating reagent having an iodoacetamide group (e.g., SUNBRIGHT ME-300IA (trade name), NOF Corp.). (6) A ω-aminocarboxylic acid, an α-amino acid or the like is introduced as a linker to the N-terminal amino group of a GIP receptor agonist peptide , and an amino group derived from this linker is reacted with a PEGylating reagent having an active ester (e.g., SUNBRIGHT MEGC-30TS (trade name), NOF Corp.). (7) A ω-aminocarboxylic acid, an α-amino acid or the like is introduced as a linker to the N-terminal amino group of a GIP receptor agonist peptide, and an amino group derived 59057274.1from this linker is reacted with a PEGylating reagent having an aldehyde group (e.g., SUNBRIGHT ME-300AL (trade name), NOF Corp.).

[0432] In addition, the GIP receptor agonist peptide may be a solvate (e.g., hydrate) or a non-solvate (e.g., non-hydrate).

[0433] The GIP receptor agonist peptide may be labeled with an isotope (e.g., 3H, 14C, 35S,125I) or the like.

[0434] Furthermore, GIP receptor agonist peptide may be a deuterium substitution formwherein1H is substituted to2H(D).

[0435] In some embodiments, a GIP receptor agonist peptide labeled with or substituted withan isotope can be used as, for example, a tracer (PET tracer) for use in Positron Emission Tomography (PET), and is useful in the fields of medical diagnosis and the like.

[0436] For the GIP receptor agonist peptide mentioned herein, the left end is the N-terminal(amino terminal) and the right end is the C-terminal (carboxyl terminal) in accordance with the conventional peptide marking. The C-terminal of peptide may be any of an amide (-CONH2), a carboxyl group (-COOH), a carboxylate (-COO-), an alkylamide (-CONHRa), and an ester (- COORa). In some embodiments, the C-terminal is amide (-CONH2).

[0437] A GIP receptor agonist peptide of the present disclosure may be in a salt form.59057274.1Examples of such salt include metal salts, ammonium salts, salts with organic base, salts with inorganic acid, salts with organic acid, salts with basic or acidic amino acid, and the like.

[0438] Examples of the metal salt include alkali metal salts such as sodium salt, potassiumsalt and the like; alkaline earth metal salts such as calcium salt, magnesium salt, barium salt and the like; aluminum salt and the like.

[0439] Examples of the salt with organic base include salts with trimethylamine,triethylamine, pyridine, picoline, 2,6-lutidine, ethanolamine, diethanolamine, triethanolamine, cyclohexylamine, dicyclohexylamine, N,N-dibenzylethylenediamine and the like.

[0440] Examples of the salt with inorganic acid include salts with hydrochloric acid,hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid and the like.

[0441] Examples of the salt with organic acid include salts with formic acid, acetic acid,trifluoroacetic acid, phthalic acid, fumaric acid, oxalic acid, tartaric acid, maleic acid, citric acid, succinic acid, malic acid, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid and the like.

[0442] Examples of the salt with basic amino acid include salts with arginine, lysine,ornithine and the like. Examples of the salt with acidic amino acid include salts with aspartic acid, glutamic acid and the like. 59057274.1

[0443] Among the above-mentioned salts, a pharmaceutically acceptable salt is of interest.For example, when a compound has an acidic functional group, an inorganic salt such as alkali metal salt (e.g., sodium salt, potassium salt etc.), alkaline earth metal salt (e.g., calcium salt, magnesium salt, barium salt etc.) and the like, ammonium salt etc., and when a compound has a basic functional group, for example, a salt with inorganic acid such as hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid and the like, or a salt with organic acid such as acetic acid, phthalic acid, fumaric acid, oxalic acid, tartaric acid, maleic acid, citric acid, succinic acid, methanesulfonic acid, p-toluenesulfonic acid and the like are some examples. In some embodiments, provided is the GIP receptor agonist peptide and an acetic acid salt thereof.

[0444] In some embodiments, the GIP receptor agonist peptide may be synthesized and / orused in a prodrug form to treat or prevent a disease of the present disclosure, for example, diabetes, obesity and / or emesis. A prodrug means a compound which is converted to a GIP receptor agonist peptide with a reaction due to an enzyme, gastric acid, etc. under the physiological condition in the living body, that is, a compound which is converted to a GIP receptor agonist peptide with oxidation, reduction, hydrolysis, etc. according to an enzyme; a polypeptide which is converted to GIP receptor agonist peptide by hydrolysis etc. due to gastric 59057274.1acid, etc.

[0445] Examples of a prodrug of a GIP receptor agonist peptide may include a compoundwherein an amino group of a GIP receptor agonist peptide is acylated, alkylated or phosphorylated (e.g., compound wherein amino group of a GIP receptor agonist peptide is eicosanoylated, alanylated, pentylaminocarbonylated, (5-methyl-2-oxo-1,3-dioxolen-4- yl)methoxycarbonylated, tetrahydrofuranylated, pyrrolidylmethylated, pivaloyloxymethylated or tert-butylated, and the like); a compound wherein a hydroxy group of a GIP receptor agonist peptide is acylated, alkylated, phosphorylated or borated (e.g., a compound wherein a hydroxy group of a GIP receptor agonist peptide is acetylated, palmitoylated, propanoylated, pivaloylated, succinylated, fumarylated, alanylated or dimethylaminomethylcarbonylated); a compound wherein a carboxy group of a GIP receptor agonist peptide is esterified or amidated (e.g., a compound wherein a carboxy group of a GIP receptor agonist peptide is C1-6alkyl esterified, phenyl esterified, carboxymethyl esterified, dimethylaminomethyl esterified, pivaloyloxymethyl esterified, ethoxycarbonyloxyethyl esterified, phthalidyl esterified, (5-methyl-2-oxo-1,3- dioxolen-4-yl)methyl esterified, cyclohexyloxycarbonylethyl esterified or methylamidated) and the like. Among others, a compound wherein a carboxy group of a GIP receptor agonist peptide is esterified with C1-6alkyl such as methyl, ethyl, tert-butyl or the like may be used. These 59057274.1compounds, peptides and polypeptides can be produced from a GIP receptor agonist peptide by a method known per se.

[0446] A prodrug of a GIP receptor agonist peptide may also be one which is converted intoa GIP receptor agonist peptide under a physiological condition, such as those described in IYAKUHIN no KAIHATSU (Development of Pharmaceuticals), Vol.7, Design of Molecules, p. 163-198, Published by HIROKAWA SHOTEN (1990).

[0447] In the present specification, the prodrug may form a salt. Examples of such a saltinclude those exemplified as the salt of a GIP receptor agonist peptide.

[0448] In some embodiments, a GIP receptor agonist peptide of the present disclosure maybe synthesized and / or used as a crystal. Crystals having a singular crystal form or a mixture of plural crystal forms are also encompassed by the examples of GIP receptor agonist peptides. Crystals can be produced by crystallizing a GIP receptor agonist peptide according to a crystallization method known per se.

[0449] In addition, a GIP receptor agonist peptide may be a pharmaceutically acceptablecocrystal or cocrystal salt. Here, the cocrystal or cocrystal salt means a crystalline substance consisting of two or more particular substances which are solids at room temperature, each having different physical properties (e.g., structure, melting point, heat of melting, 59057274.1hygroscopicity, solubility, stability, etc.). The cocrystal and cocrystal salt can be produced by cocrystallization known per se.

[0450] The crystal of a GIP receptor agonist peptide of the present disclosure is superior inphysicochemical properties (e.g., melting point, solubility, stability) and biological properties (e.g., pharmacokinetics (absorption, distribution, metabolism, excretion), efficacy expression), and thus it is extremely useful as a medicament.

[0451] In some embodiments, a GIP receptor agonist peptide and / or a prodrug thereof(hereinafter to be sometimes abbreviated as a GIP receptor agonist peptide of the present disclosure) have a GIP receptor activating action, and may have selectivity as agonists of the GIP receptor over other receptors such as the GLP1R. The compounds of the present disclosure have a high selective GIP receptor activation action in vivo.

[0452] C. METHODS OF PROPHYLAXIS AND TREATMENT OF GIP MEDIATEDCONDITIONS, DISEASES, AND DISORDERS

[0453] GIP is a gastrointestinal hormone called incretin and has a promoting action oninsulin secretion from the pancreas. Incretin is closely related to glucose metabolism and thus the compound having a GIP receptor activation action is useful for preventing and treating symptoms related to abnormal glucose metabolism including diabetes and obesity. Additionally, 59057274.1the compounds of the present disclosure have a selective GIP receptor activation action and suppresses vomiting by activating GABAergic neurons in the area postrema.

[0454] More specifically, the GIP receptor agonist peptides of the present disclosure have ahypoglycemic action, an antiemetic action, and the like.

[0455] The GIP receptor agonist peptides of the present disclosure have a high chemicalstability and excellent persistence of the effects in vivo.

[0456] The GIP receptor agonist peptides of the present disclosure may be used as a GIPreceptor activator.

[0457] In the present disclosure, the GIP receptor activator (GIP receptor agonist) means anagent having a GIP receptor activation action. Additionally, the selective GIP receptor activator (GIP receptor peptide agonist) specifically means an agent having an EC50for the GIP receptorof 1 / 10 or less, or 1 / 100 or less, or 1 / 1000 or less, or 1 / 10000 or less, or 1 / 100,000 or less timesthe EC50 for the GLP-1 receptor.

[0458] The GIP receptor agonist peptides of the present disclosure is low in its toxicity (e.g.,acute toxicity, chronic toxicity, genetic toxicity, reproductive toxicity, cardiac toxicity, carcinogenicity), shows a few side effects, and can be safely administered to a mammal (e.g., human, bovine, horse, dog, cat, monkey, mouse, rat) as an agent for the prophylaxis or treatment 59057274.1of various diseases mentioned below and the like.

[0459] The GIP receptor agonist peptides of the present disclosure can be used as an agentfor the treatment or prophylaxis of various diseases including diabetes and obesity, by virtue of the above-mentioned activating action on GIP receptors. The GIP receptor agonist peptides of the present disclosure can be used as an agent for the prophylaxis or treatment of, for example, symptomatic obesity, obesity based on simple obesity, disease state or disease associated with obesity, eating disorder, diabetes (e.g., type 1 diabetes, type 2 diabetes, gestational diabetes, obese diabetes), hyperlipidemia (e.g., hypertriglyceridemia, hypercholesterolemia, high LDL- cholesterolemia, low HDL-cholesterolemia, postprandial hyperlipemia), hypertension, cardiac failure, diabetic complications [e.g., neuropathy, nephropathy, retinopathy, diabetic cardiomyopathy, cataract, macroangiopathy, osteopenia, hyperosmolar diabetic coma, infectious disease (e.g., respiratory infection, urinary tract infection, gastrointestinal infection, dermal soft tissue infections, inferior limb infection), diabetic gangrene, xerostomia, hypacusis, cerebrovascular disorder, peripheral blood circulation disorder], metabolic syndrome (disease states having 3 or more selected from hypertriglyceridemia, (TG), low HDL cholesterol(HDL- C)emia, hypertension, abdominal obesity and impaired glucose tolerance), sarcopenia and the like. 59057274.1

[0460] Examples of the symptomatic obesity include endocrine obesity (e.g., Cushingsyndrome, hypothyroidism, insulinoma, obese type II diabetes, pseudohypoparathyroidism, hypogonadism), central obesity (e.g., hypothalamic obesity, frontal lobe syndrome, Kleine-Levin syndrome), hereditary obesity (e.g., Prader-Willi syndrome, Laurence-Moon-Biedl syndrome), drug-induced obesity (e.g., steroid, phenothiazine, insulin, sulfonylurea (SU) agent, β-blocker- induced obesity) and the like.

[0461] Examples of the disease state or disease associated with obesity include glucosetolerance disorders, diabetes (e.g., type 2 diabetes (T2DM), obese diabetes), lipid metabolism abnormality (synonymous with the above-mentioned hyperlipidemia), hypertension, cardiac failure, hyperuricemia, gout, fatty liver (including non-alchoholic steato-hepatitis), coronary heart disease (myocardial infarction, angina pectoris), cerebral infarction (brain thrombosis, transient cerebral ischemic attack), bone / articular disease (knee osteoarthritis, hip osteoarthritis, spondylitis deformans, lumbago), sleep apnea syndrome / Pickwick syndrome, menstrual disorder (abnormal menstrual cycle, abnormality of menstrual flow and cycle, amenorrhea, abnormal catamenial symptom), metabolic syndrome and the like.

[0462] New diagnostic criteria were reported by The Japan Diabetes Society in 1999 aboutthe diagnostic criteria of diabetes. 59057274.1

[0463] According to this report, diabetes refers to a state that meets any of a fasting bloodglucose level (glucose concentration in venous plasma) of 126 mg / dl or more, a 2-hr value (glucose concentration in venous plasma) of 200 mg / dl or more in the 75 g oral glucose tolerance test (75 g OGTT), and a casual blood glucose level (glucose concentration in venous plasma) of 200 mg / dl or more. Also, a state that does not apply to the above-mentioned diabetes, and is not a state exhibiting “a fasting blood glucose level (glucose concentration in venous plasma) less than 110 mg / dl or a 2-hr value (glucose concentration in venous plasma) less than 140 mg / dl in the 75 g oral glucose tolerance test (75 g OGTT)” (normal type) is called “borderline type”.

[0464] Moreover, new diagnostic criteria were reported by American Diabetes Association(ADA) in 1997 and by World Health Organization (WHO) in 1998 about the diagnostic criteria of diabetes.

[0465] According to these reports, diabetes refers to a state that meets a fasting bloodglucose level (glucose concentration in venous plasma) of 126 mg / dl or more and a 2-hr value (glucose concentration in venous plasma) of 200 mg / dl or more in the 75 g oral glucose tolerance test.

[0466] According to the above-mentioned reports, impaired glucose tolerance refers to astate that meets a fasting blood glucose level (glucose concentration in venous plasma) less than 59057274.1126 mg / dl and a 2-hr value (glucose concentration in venous plasma) of 140 mg / dl or more and less than 200 mg / dl in the 75 g oral glucose tolerance test. According to the report of ADA, a state exhibiting a fasting blood glucose level (glucose concentration in venous plasma) of 110 mg / dl or more and less than 126 mg / dl is called IFG (Impaired Fasting Glucose). On the other hand, according to the report of WHO, a state of the IFG (Impaired Fasting Glucose) exhibiting a 2-hr value (glucose concentration in venous plasma) less than 140 mg / dl in the 75 g oral glucose tolerance test is called IFG (Impaired Fasting Glycemia).

[0467] The GIP receptor agonist peptides of the present disclosure may also be used as anagent for the prophylaxis or treatment of diabetes determined according to the above-mentioned new diagnostic criteria, borderline type diabetes, impaired glucose tolerance, IFG (Impaired Fasting Glucose) and IFG (Impaired Fasting Glycemia). Moreover, the GIP receptor agonist peptides of the present disclosure can prevent progress of borderline type, impaired glucose tolerance, IFG (Impaired Fasting Glucose) or IFG (Impaired Fasting Glycemia) into diabetes.

[0468] The GIP receptor agonist peptides of the present disclosure are also useful as an agentfor the prophylaxis or treatment of metabolic syndrome. The incidence of cardiovascular disease is significantly high in metabolic syndrome patients, compared with patients with a single lifestyle-related disease. Thus, the prophylaxis or treatment of metabolic syndrome is 59057274.1exceedingly important for preventing cardiovascular disease.

[0469] The diagnostic criteria of metabolic syndrome were announced by the WHO in 1999and by NCEP in 2001. According to the diagnostic criteria of WHO, an individual having hyperinsulinemia or abnormal glucose tolerance as a requirement and two or more of visceral obesity, dyslipidemia (high TG or low HDL) and hypertension is diagnosed as having metabolic syndrome (World Health Organization: Definition, Diagnosis and Classification of Diabetes Mellitus and Its Complications. Part I: Diagnosis and Classification of Diabetes Mellitus, World Health Organization, Geneva, 1999). According to the diagnostic criteria of the Adult Treatment Panel III of the National Cholesterol Education Program (guideline of ischemic heart disease) in USA, an individual having three or more of visceral obesity, hypertriglyceridemia, low HDL- cholesterolemia, hypertension and abnormal glucose tolerance is diagnosed as having metabolic syndrome (National Cholesterol Education Program: Executive Summary of the Third Report of National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adults Treatment Panel III). The Journal of the American Medical Association, Vol.285, 2486-2497, 2001).

[0470] More specifically, the GIP receptor agonist peptides of the present disclosure have anantiemetic action, and may inhibit or reduce the number and severity of the occurrence of 59057274.1nausea, and / or vomiting when associated with various stimuli disclosed herein, for example, when a subject has cyclic vomiting syndrome or is administered a chemotherapeutic drug, for example, a chemotherapeutic drug with emetic potential, such as platinum based chemotherapeutics such as cisplatin, oxaliplatin, and carboplatin; irinotecan and other topo isomerase inhibitors used in the treatment of cancer. The GIP receptor agonist peptides of the present disclosure have a high chemical stability and excellent persistence of the effects in vivo.

[0471] The GIP receptor agonist peptides of the present disclosure may be used as a GIPreceptor activator. In the present disclosure, the GIP receptor activator (GIP receptor agonist) means an agent having a GIP receptor activation action. Additionally, the selective GIP receptor activator (i.e. a GIP receptor agonist as used herein) specifically means an agent having an EC50for the GIP receptor of 1 / 1000 or less, or 1 / 10000 or less, or 1 / 100,000 times the EC50for the GLP-1 receptor, or in other words the ratio of EC50GLP1R / EC50GIPR is greater than 10, greater than 100, or greater than 1,000, or greater than 10,000, or greater than 100,000, or from 100 to 1,000,000 or more.

[0472] The GIP receptor agonist peptides of the present disclosure have low toxicity (e.g.,acute toxicity, chronic toxicity, genetic toxicity, reproductive toxicity, cardiac toxicity, carcinogenicity), shows a few side effects, and can be safely administered to a mammal (e.g., 59057274.1human, bovine, horse, dog, cat, monkey, mouse, rat) as an agent for the prophylaxis or treatment of emesis.

[0473] "Treatment," in the context of treating emesis by administering at least one of the GIPreceptor agonist peptides disclosed herein, includes both prophylactic treatment and the treatment of emesis after a subject experiences emesis. Prophylactic treatment includes administration of a GIP receptor agonist peptide before a subject experiences emesis, such as when the subject experiences nausea, as well as administration of the GIP receptor agonist peptide before the subject is exposed to a substance, agent, or event, or before the subject contracts a condition, which results in or is likely to result in the subject experiencing emesis. As used herein, "therapeutically effective amount" refers to an amount of the GIP receptor agonist peptide sufficient to elicit the desired biological response. In the present disclosure, the desired biological response is treating and / or preventing an abnormal glucose metabolism in a subject, for example, in a subject in need thereof, including diabetes and obesity, or the prevention and / or treatment of emesis in a subject in need thereof.

[0474] The compounds disclosed herein can also be used for secondary prevention orsuppression of progression of the above-mentioned various diseases (e.g., cardiovascular events such as myocardial infarction and the like). In addition, the compounds disclosed herein is also 59057274.1useful as a feeding suppressant and a weight reducing agent. The compounds disclosed herein can also be used in combination with a diet therapy (e.g., diet therapy for diabetes), and an exercise therapy. The GIP receptor agonist peptides of the present disclosure can be used to treat or prevent diabetes and / or obesity, a pathophysiological condition related to diabetes and / or obesity, emesis, for example, when a subject experiences or is about to experience emesis, such as nausea and / or vomiting. In various embodiments, the subject, for example, a mammal, for example, humans, non-human primates, apes, monkeys, laboratory mammals for example, mice, rats, rabbits, guinea-pigs, ferrets, domesticated mammals, such as companion mammals, dogs, cats and horses, and farm mammals, such as cattle, pigs, sheep and goats purely as examples, but not intended to be an exhaustive list, may be treated with a GIP receptor agonist peptide of the present disclosure. In each of these cases, the methods of the present disclosure are provided to treat or prevent diabetes, obesity, or emesis, for example, nausea and / or vomiting in a subject in need thereof, to reduce or inhibit diabetes, obesity, or emesis, to reduce or inhibit a symptom associated with diabetes, obesity, or emesis, or to reduce or inhibit a pathological condition or symptom associated with diabetes, obesity, or emesis, for example, nausea and / or vomiting.

[0475] In order to prevent or treat emesis, an effective amount of one or more of the presentcompounds in a pharmaceutical composition is administered once per day, for example, once per 59057274.124 hours, to a subject / patient (used interchangeably herein) in need thereof. A subject is determined to be in need of treatment with the present GIP receptor agonist peptide either through observation of vomiting by the subject, or through a subject's self-reporting of emesis (in the case of a human subject). A patient is determined to be in need of preventative therapy by assessing that the patient is at risk of experiencing emesis due to another medical condition or due to exposure to an agent known to be associated with emesis, such as an infection by a virus or bacteria or chemical agent or radiation.

[0476] The present GIP receptor agonist peptides are beneficial in the therapy of acute,delayed or anticipatory emesis, including emesis induced by chemotherapy, radiation, toxins, viral or bacterial infections, pregnancy, vestibular disorders (e.g. motion sickness, vertigo, dizziness and Meniere's disease), surgery, pain, opioid use and withdrawal, migraine, and variations in intracranial pressure. The uses of the compounds disclosed herein are of benefit in the therapy of emesis induced by radiation, for example during the treatment of cancer, or radiation sickness, and in the treatment of post-operative nausea and vomiting. Most especially, use of the compounds disclosed herein is beneficial in the therapy of emesis induced by antineoplastic (cytotoxic) agents including those routinely used in cancer chemotherapy, emesis induced by other pharmacological agents, for example, alpha-2 adrenoceptor antagonists, such as 59057274.1yohimbine, MK-912 and MK-467, and type IV cyclic nucleotide phosphodiesterase (PDE4) inhibitors, such as RS14203, CT-2450 and rolipram.

[0477] Examples of chemotherapeutic agents are described, for example, by D. J. Stewart inNausea and Vomiting: Recent Research and Clinical Advances, ed. J. Kucharczyk et al., CRC Press Inc., Boca Raton, Fla., USA, 1991, pages 177-203, especially page 188. Commonly used chemotherapeutic agents include cisplatin, carboplatin, oxaliplatin, cyclophosphamide, dacarbazine (DTIC), dactinomycin, mechlorethamine (nitrogen mustard), streptozocin, cyclophosphamide, carmustine (BCNU), irinotecan, and other topoisomerase inhibitors, lomustine (CCNU), doxorubicin (adriamycin), daunorubicin, procarbazine, mitomycin, cytarabine, etoposide, methotrexate, 5-fluorouracil, vinblastine, vincristine, bleomycin, paclitaxel and chlorambucil (R. J. Gralle et al. in Cancer Treatment Reports, 1984, 68, 163-172). Emesis due to other chemical agents, such as the toxins soman or sarin, or opioid drug usage and / or withdrawal, e.g. morphine, heroin, oxycodone, and the like can also be prevented and / or treated.

[0478] The present compounds are administered to a patient in a quantity sufficient to treator prevent the symptoms and / or underlying etiology associated with emesis in the patient. In a preferred embodiment, the GIP receptor agonist peptides are administered prior to administration of an agent which is likely to cause emesis, such as one or more of the chemotherapeutic agents 59057274.1described above. The present GIP receptor agonist peptides can also be administered in combination with such agents, either in physical combination or in combined therapy through the administration of the present compounds and agents in succession (in any order). Although the presently disclosed compounds and forms thereof are useful in any mammal suffering from emesis, a preferred subject is a human.

[0479] In some embodiments, the selective GIPr agonists of the present disclosure may beadministered to treat emesis when a subject is concomitantly being treated for diabetes and / or obesity. Several known anti-diabetic medicaments are known for causing emesis, for example, Metformin (Glucophage, Glumetza, others), sulfonylureas, meglitinides, thiazolidinediones, DPP-4 inhibitors, SGLT2 inhibitors, and GLP-1 receptor agonists. In some embodiments, methods for treating emesis in a subject, for example in a subject in need thereof, may include administering an effective amount of a GIP receptor agonist peptide to a subject that does not have type-2 diabetes mellitus or a subject that is not taking a medicament to treat type-2 diabetes mellitus while experiencing emesis.

[0480] Nausea is a subjective unpleasant feeling in the back of one’s throat and stomach thatmay lead to vomiting. There are many words that describe nausea including, but not limited to: sick to my stomach, queasy, or upset stomach. Nausea can have other symptoms that happen at 59057274.1the same time, such as increased saliva (spit), dizziness, light-headedness, trouble swallowing, skin temperature changes, and a fast heart rate. Vomiting is also described as “throwing up.” When one vomits, one’s stomach muscles contract (squeeze) and push the contents of one’s stomach out through their mouth. One might or might not feel nauseated. Retching is when one tries to vomit without bringing anything up from one’s stomach. Other words used to describe retching are gagging or dry heaves. Nausea and vomiting often happen at the same time, but they can be 2 different conditions that may be mutually exclusive or mutually associated. Some chemotherapy drugs are more likely to cause nausea and vomiting than others. Doctors classify chemotherapy drugs according to their emetogenic potential (how likely the drug will cause nausea or vomiting) as high, moderate, low, or minimal risk.

[0481] In various embodiments, the GIPR agonist peptide compounds may be dosed onceper day to provide treatment and prophylactic treatment against emesis and emesis related symptoms. The peptide compounds of the present disclosure may be used to preferentially treat cyclic vomiting syndrome (CVS); chemotherapy induced nausea and vomiting (CINV) and post- operative nausea and vomiting (PONV). Cyclic vomiting syndrome (CVS) is a chronic functional gastrointestinal disorder that is being increasingly recognized in adults. It is characterized by episodic nausea and vomiting and is associated with significant morbidity. 59057274.1

[0482] An estimated 80% of patients with cancer will experience chemotherapy-inducednausea and vomiting (CINV). The term CINV includes emesis and nausea, which can involve a loss of appetite and result in decreased oral intake of fluids and calories. Five different types of CINV have been defined and include acute, delayed, breakthrough, anticipatory, and refractory CINV.

[0483] Postoperative nausea and vomiting (PONV) is the phenomenon of nausea, vomitingor retching experienced by a patient in the Post Anesthesia Care Unit (PACU) or 24-hours following a surgical procedure. It is an unpleasant complication that affects about 10% of the population undergoing general anaesthesia each year.

[0484] In an exemplary embodiment, the present disclosure provides for the prophylactictreatment or maintenance therapy for cyclic vomiting syndrome (CVS); chemotherapy induced nausea and vomiting (CINV) and post-operative nausea and vomiting (PONV), comprising administering one or more GIPR agonist peptide compounds of the present disclosure.

[0485] In an exemplary embodiment, the present disclosure provides for the prophylactictreatment or maintenance therapy for cyclic vomiting syndrome (CVS); chemotherapy induced nausea and vomiting (CINV) and post-operative nausea and vomiting (PONV), comprising administering one or more GIPR agonist peptide compounds of the present disclosure in a 59057274.1therapeutically effective amount to a subject in need thereof.

[0486] The GIP receptor agonist peptides of the present disclosure may be used as apreventive / therapeutic agent, i.e. prophylactic treatment or maintenance therapy for vomiting and / or nausea caused, for example, by clinical pathological conditions or causes described in the following

[0487] The GIP receptor agonist peptides of the present disclosure may be used as apreventive / therapeutic agent for vomiting and / or nausea caused, for example, by clinical pathological conditions or causes described in the following (1) to (10). Additionally, the GIP receptor agonist peptide of the present disclosure may be used as a preventive / therapeutic agent for chronic unexplained nausea and vomiting. The vomiting or nausea also includes imminent unpleasant sensations of wanting to eject the contents of the stomach through the mouth such as feeling queasy and retching, and may also be accompanied by autonomic symptoms such as facial pallor, cold sweat, salivary secretion, tachycardia, and diarrhea. The vomiting also includes acute vomiting, protracted vomiting, and anticipatory vomiting.

[0488] In some embodiments, the present disclosure provides GIP receptor agonist peptides,or a pharmaceutically acceptable salt thereof, medicaments, pharmaceutical compositions, and methods for the prevention and / or treatment of emesis, vomiting, or nausea caused by one or 59057274.1more conditions or causes selected from the following group consisting of non-limiting examples (1) to (10): (1) Diseases accompanied by vomiting or nausea such as gastroparesis, gastrointestinal hypomotility, peritonitis, abdominal tumor, constipation, gastrointestinal obstruction, chronic intestinal pseudo-obstruction, functional dyspepsia, cyclic vomiting syndrome, chronic unexplained nausea and vomiting, acute pancreatitis, chronic pancreatitis, hepatitis, hyperkalemia, cerebral edema, intracranial lesion, metabolic disorder, gastritis caused by an infection, postoperative disease, myocardial infarction, migraine, intracranial hypertension, and intracranial hypotension (e.g., altitude sickness); (2) Vomiting and / or nausea induced by chemotherapeutic drugs such as (i) alkylating agents (e.g., cyclophosphamide, carmustine, lomustine, chlorambucil, streptozocin, dacarbazine, ifosfamide, temozolomide, busulfan, bendamustine, and melphalan), cytotoxic antibiotics (e.g., dactinomycin, doxorubicin, mitomycin-C, bleomycin, epirubicin, actinomycin D, amrubicin, idarubicin, daunorubicin, and pirarubicin), antimetabolic agents (e.g., cytarabine, methotrexate, 5-fluorouracil, enocitabine, and clofarabine), vinca alkaloids (e.g., etoposide, vinblastine, and vincristine), other chemotherapeutic agents such as cisplatin, procarbazine, hydroxyurea, azacytidine, 59057274.1irinotecan, interferon α, interleukin-2, oxaliplatin, carboplatin, nedaplatin, and miriplatin; (ii) opioid analgesics (e.g., morphine); (iii) dopamine receptor D1D2 agonists (e.g., apomorphine); and (iv) cannabis and cannabinoid products including cannabis hyperemesis syndrome; (3) Vomiting or nausea caused by radiation sickness or radiation therapy for the chest, the abdomen, or the like used to treat cancers; (4) Vomiting or nausea caused by a poisonous substance or a toxin; (5) Vomiting and nausea caused by pregnancy including hyperemesis gravidarium; and (6) Vomiting and nausea caused by a vestibular disorder such as motion sickness or dizziness (7) Opioid withdrawal; (8) A vestibular disorder such as motion sickness or dizziness; and (9) A physical injury causing local, systemic, acute or chronic pain. These causes of emesis, or nausea, or vomiting are not meant to be exhaustive. Other conditions, activities, side effects may cause emesis, for example, nausea and / or vomiting. Nausea can be measured in ways known to the art, such as through the use of a visual analog scale (VAS). 59057274.1

[0489] In some embodiments, the present disclosure provides GIP receptor agonist peptides,or a pharmaceutically acceptable salt thereof, medicaments, pharmaceutical compositions, and methods for the prevention and / or treatment of emesis, vomiting, or nausea as a result of cyclic vomiting syndrome or chemotherapy.

[0490] In some embodiments, the present disclosure provides GIP receptor agonist peptides,or a pharmaceutically acceptable salt thereof, medicaments, pharmaceutical compositions, and methods for the prevention and / or treatment of emesis, vomiting, or nausea wherein the subject is a non-type 2 diabetes mellitus subject.

[0491] In some embodiments, the present disclosure provides GIP receptor agonist peptides,or a pharmaceutically acceptable salt thereof, medicaments, pharmaceutical compositions, and methods for the prevention and / or treatment of emesis, vomiting, or nausea wherein the subject has normal baseline health measurements following the administering.

[0492] In some embodiments, the present disclosure provides GIP receptor agonist peptides,or a pharmaceutically acceptable salt thereof, medicaments, pharmaceutical compositions, and methods for the prevention and / or treatment of emesis, vomiting, or nausea wherein the emesis is delayed emesis or anticipatory emesis. 59057274.1

[0493] In some embodiments, the present disclosure provides GIP receptor agonist peptides,or a pharmaceutically acceptable salt thereof, medicaments, pharmaceutical compositions, and methods for the prevention and / or treatment of emesis, vomiting, or nausea.

[0494] In some embodiments, the present disclosure provides GIP receptor agonist peptides,or a pharmaceutically acceptable salt thereof, medicaments, pharmaceutical compositions, and methods for the prevention and / or treatment of emesis, vomiting, or nausea wherein the emesis is treated in the subject without inducing anxiety or sedation in the subject.

[0495] In some embodiments, the present disclosure provides GIP receptor agonist peptides,or a pharmaceutically acceptable salt thereof, medicaments, pharmaceutical compositions, and methods for the prevention and / or treatment of emesis, vomiting, or nausea wherein the emesis is treated in the subject without inducing suppression of glucagon secretion when plasma glucose levels are above fasting levels.

[0496] In some embodiments, the present disclosure provides GIP receptor agonist peptides,or a pharmaceutically acceptable salt thereof, medicaments, pharmaceutical compositions, and methods for the prevention and / or treatment of emesis, vomiting, or nausea wherein the emesis is treated in the subject without substantially activating the GLP-1 receptor. 59057274.1

[0497] In some embodiments, the present disclosure provides GIP receptor agonist peptides,or a pharmaceutically acceptable salt thereof, medicaments, pharmaceutical compositions, and methods for the prevention and / or treatment of emesis, vomiting, or nausea wherein the emesis is treated in the subject without concomitant, subsequent, or prior administration of a GLP-1 receptor agonist.

[0498] In some embodiments, the present disclosure provides GIP receptor agonist peptides,or a pharmaceutically acceptable salt thereof, medicaments, pharmaceutical compositions, and methods for the prevention and / or treatment of emesis, vomiting, or nausea wherein the emesis is treated in a subject not taking a medicament to control a metabolic syndrome disorder.

[0499] In some embodiments, the present disclosure provides GIP receptor agonist peptides,or a pharmaceutically acceptable salt thereof, medicaments, pharmaceutical compositions, and methods for the prevention and / or treatment of emesis, vomiting, or nausea wherein the emesis is treated in a subject taking a medicament to control a metabolic syndrome disorder.

[0500] In some embodiments, the present disclosure provides GIP receptor agonist peptides,or a pharmaceutically acceptable salt thereof, medicaments, pharmaceutical compositions, and methods for the prevention and / or treatment of emesis, vomiting, or nausea wherein the metabolic syndrome disorder is type 2 diabetes mellitus or obesity. 59057274.1

[0501] In some embodiments, the present disclosure provides GIP receptor agonist peptides,or a pharmaceutically acceptable salt thereof, medicaments, pharmaceutical compositions, and methods for the prevention and / or treatment of emesis, vomiting, or nausea wherein the emesis is caused by or causes cyclic vomiting syndrome, or nausea or vomiting associated with chemotherapy.

[0502] In some embodiments, the present disclosure provides GIP receptor agonist peptides,or a pharmaceutically acceptable salt thereof, medicaments, pharmaceutical compositions, and methods for the prevention and / or treatment of emesis, vomiting, or nausea wherein the emesis, vomiting, or nausea is a result of having the subject is a subject being treated for cancer, and the subject is administered chemotherapy or a chemotherapeutic agent said chemotherapy or a chemotherapeutic agent comprises: (i) alkylating agents (e.g., cyclophosphamide, carmustine, lomustine, chlorambucil, streptozocin, dacarbazine, ifosfamide, temozolomide, busulfan, bendamustine, and melphalan), cytotoxic antibiotics (e.g., dactinomycin, doxorubicin, mitomycin-C, bleomycin, epirubicin, actinomycin D, amrubicin, idarubicin, daunorubicin, and pirarubicin), antimetabolic agents (e.g., cytarabine, methotrexate, 5-fluorouracil, enocitabine, and clofarabine), vinca alkaloids (e.g., etoposide, vinblastine, and vincristine), other chemotherapeutic agents such as cisplatin, procarbazine, hydroxyurea, azacytidine, irinotecan, 59057274.1interferon α, interleukin-2, oxaliplatin, carboplatin, nedaplatin, and miriplatin; (ii) opioid analgesics (e.g., morphine); (iii) dopamine receptor D1D2 agonists (e.g., apomorphine); (iv) cannabis and cannabinoid products including cannabis hyperemesis syndrome.

[0503] In some embodiments, the present disclosure provides GIP receptor agonist peptides,or a pharmaceutically acceptable salt thereof, medicaments, pharmaceutical compositions, and methods for the prevention and / or treatment of emesis, vomiting, or nausea wherein the subject has type 2 diabetes mellitus.

[0504] In some embodiments, the present disclosure provides GIP receptor agonist peptides,or a pharmaceutically acceptable salt thereof, medicaments, pharmaceutical compositions, and methods for the prevention and / or treatment of emesis, vomiting, or nausea wherein the GIP receptor agonist peptide or medicament is administered subcutaneously, intravenously, intramuscularly, intraperitonealy, orally or via inhalation.

[0505] In some embodiments, the present disclosure provides GIP receptor agonist peptides,or a pharmaceutically acceptable salt thereof, medicaments, pharmaceutical compositions, and methods for the prevention and / or treatment of emesis, vomiting, or nausea wherein the GIP receptor agonist peptide or medicament is administered subcutaneously or intravenously. 59057274.1

[0506] In some embodiments, the present disclosure provides GIP receptor agonist peptides,or a pharmaceutically acceptable salt thereof, medicaments, pharmaceutical compositions, and methods for the prevention and / or treatment of emesis, vomiting, or nausea wherein the GIP receptor agonist peptide or medicament is administered subcutaneously.

[0507] In some embodiments, the present disclosure provides GIP receptor agonist peptides,or a pharmaceutically acceptable salt thereof, medicaments, pharmaceutical compositions, and methods for the prevention and / or treatment of emesis, vomiting, or nausea in a mammalian subject, for example, a companion animal, a laboratory mammal, a primate mammal, or a non- primate mammal. In some embodiments, the subject is human.

[0508] In some embodiments, the present disclosure provides GIP receptor agonist peptides,or a pharmaceutically acceptable salt thereof, medicaments, pharmaceutical compositions, and methods for the prevention and / or treatment of emesis, vomiting, or nausea wherein the GIP receptor agonist peptide or medicament is administered to the subject before, during, or after the subject develops the emesis, the vomiting, the nausea, or the one or more conditions or causes in examples 1-10 described above.

[0509] The GIP receptor agonist peptide of the present disclosure can also be used forsecondary prevention or suppression of progression of the above-mentioned various diseases, or 59057274.1conditions (e.g., cardiovascular events such as myocardial infarction and the like). In addition, the compounds disclosed herein is also useful as a feeding suppressant and a weight reducing agent. The compounds disclosed herein can also be used in combination with a diet therapy (e.g., diet therapy for diabetes), and an exercise therapy.

[0510] In some embodiments, the present disclosure provides GIP receptor agonist peptides,or a pharmaceutically acceptable salt thereof, medicaments, pharmaceutical compositions, and methods for the prevention and / or treatment of emesis, vomiting, or nausea for example, which is administered to treat emesis as a monotherapy.

[0511] In some embodiments, the present disclosure provides GIP receptor agonist peptides,or a pharmaceutically acceptable salt thereof, medicaments, pharmaceutical compositions, and methods for the prevention and / or treatment of emesis, vomiting, or nausea for example, which is administered to a subject Q1D, or once per 24 hours, to treat or prevent emesis, including vomiting and / or nausea.

[0512] In some embodiments, the present disclosure provides GIP receptor agonist peptides,or a pharmaceutically acceptable salt thereof, medicaments, pharmaceutical compositions, and methods for the prevention and / or treatment of emesis, vomiting, or nausea for example, which is administered for use in suppressing vomiting or nausea. 59057274.1

[0513] In some embodiments, the present disclosure provides GIP receptor agonist peptides,or a pharmaceutically acceptable salt thereof, medicaments, pharmaceutical compositions, for the manufacture of a suppressant for vomiting or nausea.

[0514] In some embodiments, the present disclosure provides GIP receptor agonist peptides,or a pharmaceutically acceptable salt thereof, medicaments, pharmaceutical compositions, and methods for activation of a GIP receptor, wherein the method comprises administering a GIP receptor agonist peptide, or medicament, or pharmaceutical compositions to a subject.

[0515] In some embodiments, the present disclosure provides methods of preventing ortreating emesis in a subject, the method comprising administering to the subject an effective amount of the GIP receptor agonist peptide, or a pharmaceutically acceptable salt thereof, or a medicament, or the pharmaceutical composition formulated with a GIP receptor agonist peptide, or a pharmaceutically acceptable salt thereof of the present disclosure, for example, a GIP receptor agonist peptide, or a pharmaceutically acceptable salt thereof as provided in Formulae (I), (I-A) and / or (I-B).

[0516] In some embodiments, the methods disclosed herein are effective in the treatmentand / or prevention of emesis, wherein the emesis includes nausea and / or vomiting, and wherein the method includes activating of a GIP receptor, in the subject administered with a GIP receptor 59057274.1agonist peptide of the present disclosure, for example, one or more GIP receptor agonist peptides, or a pharmaceutically acceptable salts thereof as provided in Formulae (I), (I-A) and / or (I-B).

[0517] D. FORMULATIONS

[0518] A medicament containing a GIP receptor agonist peptide of the present disclosureshows low toxicity and is obtained using the compound of the present disclosure alone or in admixture with a pharmacologically acceptable carrier according to a method known per se (e.g., the method described in the Japanese Pharmacopoeia) generally used as production methods of pharmaceutical preparations, and safely administered orally or parenterally (e.g., topically, rectally, intravenously administered) as a pharmaceutical preparation, for example, tablets (inclusive of sugar-coated tablets, film-coated tablets, sublingual tablets, orally disintegrating tablets), powders, granules, capsules (inclusive of soft capsules, microcapsules), liquids, troches, syrups, emulsions, suspensions, injections (e.g., subcutaneous injections, intravenous injections, intramuscular injections, intraperitoneal injections etc.), external preparations (e.g., transnasal preparations, dermal preparations, ointments), suppository (e.g., rectal suppositories, vaginal suppositories), pellets, nasal preparations, pulmonary preparations (inhalants), transfusions and the like. 59057274.1

[0519] These preparations may be controlled release preparations such as a rapid releasepreparation, a sustained release preparation and the like (e.g., a sustained release microcapsule). The content of the compound of the present disclosure in a pharmaceutical preparation is about 0.01 - about 100 wt% of the whole preparation.

[0520] The above-mentioned pharmaceutically acceptable carrier may be exemplified byvarious organic or inorganic carrier materials that are conventionally used as preparation materials, for example, excipient, lubricant, binding agent and disintegrant for solid preparations; or solvent, solubilizing agent, suspending agent, isotonic agent, buffering agent, soothing agent and the like for liquid preparations. Further, if necessary, general additives such as preservative, antioxidant, colorant, sweetening agent, adsorbing agent, wetting agent and the like can be also used appropriately in a suitable amount.

[0521] Examples of the excipient include lactose, sucrose, D-mannitol, starch, corn starch,crystalline cellulose, light anhydrous silicic acid and the like.

[0522] Examples of the lubricant include magnesium stearate, calcium stearate, talc,colloidal silica and the like. 59057274.1

[0523] Examples of the binding agent include crystalline cellulose, sucrose, D-mannitol,dextrin, hydroxypropylcellulose, hydroxypropylmethylcellulose, polyvinylpyrrolidone, starch, sucrose, gelatin, methylcellulose, carboxymethylcellulose sodium and the like.

[0524] Examples of the disintegrant include starch, carboxymethylcellulose,carboxymethylcellulose calcium, carboxymethylstarch sodium, L-hydroxypropylcellulose and the like.

[0525] Examples of the solvent include water for injection, alcohol, propylene glycol,Macrogol, sesame oil, corn oil, olive oil and the like.

[0526] Examples of the solubilizing agent include polyethylene glycol, propylene glycol, D-mannitol, benzyl benzoate, ethanol, trisaminomethane, cholesterol, triethanolamine, sodium carbonate, sodium citrate and the like.

[0527] Examples of the suspending agent include surfactants such as stearyl triethanolamine,sodium lauryl sulfate, laurylaminopropionic acid, lecithin, benzalkonium chloride, benzetonium chloride, glycerin monostearate and the like; hydrophilic polymers such as polyvinyl alcohol, polyvinylpyrrolidone, carboxymethylcellulose sodium, methylcellulose, hydroxymethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose and the like; and the like. 59057274.1

[0528] Examples of the isotonic agent include glucose, D-sorbitol, sodium chloride, glycerin,D-mannitol and the like.

[0529] Examples of the buffering agent include buffer solutions such as phosphates, acetates,carbonates, citrates and the like.

[0530] Examples of the soothing agent include benzyl alcohol and the like.

[0531] Examples of the preservative include parahydroxybenzoic acid esters, chlorobutanol,benzyl alcohol, phenethyl alcohol, dehydroacetic acid, sorbic acid and the like.

[0532] Examples of the antioxidant include sulfites, ascorbic acid, α-tocopherol and the like.

[0533] Examples of the colorant include water-soluble food coal tar dyes (e.g., food dyessuch as Food Red No.2 and No.3, Food Yellow No.4 and No.5, Food Blue No.1 and No.2, and the like), water-insoluble lake dyes (e.g., aluminum salts of the aforementioned water- soluble Food coal tar dyes), natural dyes (e.g., β-carotene, chlorophyll, ferric oxide red) and the like.

[0534] Examples of the sweetening agent include saccharin sodium, dipotassiumglycyrrhizinate, aspartame, stevia and the like. 59057274.1

[0535] Examples of the adsorbing include porous starch, calcium silicate (trade name: FloriteRE), magnesium alumino metasilicate (trade name: Neusilin) and light anhydrous silicic acid (trade name: Sylysia).

[0536] Examples of the wetting agent include propylene glycol monostearate, sorbitanmonooleate, diethylene glycol monolaurate and polyoxyethylenelauryl ether.

[0537] During production of an oral preparation, coating may be applied as necessary for thepurpose of masking of taste, enteric property or durability.

[0538] Examples of the coating base to be used for coating include sugar coating base,aqueous film coating base, enteric film coating base and sustained-release film coating base.

[0539] As the sugar coating base, sucrose is used. Moreover, one or more kinds selectedfrom talc, precipitated calcium carbonate, gelatin, gum arabic, pullulan, carnauba wax and the like may be used in combination.

[0540] Examples of the aqueous film coating base include cellulose polymers such ashydroxypropyl cellulose, hydroxypropylmethyl cellulose, hydroxyethyl cellulose, methylhydroxyethyl cellulose etc.; synthetic polymers such as polyvinylacetal diethylaminoacetate, aminoalkyl methacrylate copolymer E [Eudragit E (trade name)], polyvinylpyrrolidone etc.; and polysaccharides such as pullulan etc. 59057274.1

[0541] Examples of the enteric film coating base include cellulose polymers such ashydroxypropylmethyl cellulose phthalate, hydroxypropylmethyl cellulose acetate succinate, carboxymethylethyl cellulose, cellulose acetate phthalate etc.; acrylic polymers such as methacrylic acid copolymer L [Eudragit L (trade name)], methacrylic acid copolymer LD [Eudragit L-30D55 (trade name)], methacrylic acid copolymer S [Eudragit S (trade name)] etc.; and naturally occurring substances such as shellac etc.

[0542] Examples of the sustained-release film coating base include cellulose polymers suchas ethyl cellulose etc.; and acrylic polymers such as aminoalkyl methacrylate copolymer RS [Eudragit RS (trade name)], ethyl acrylate-methyl methacrylate copolymer suspension [Eudragit NE (trade name)] etc.

[0543] The above-mentioned coating bases may be used after mixing with two or more kindsthereof at appropriate ratios. For coating, for example, a light shielding agent such as titanium oxide, red ferric oxide and the like can be used.

[0544] E. ADMINISTRATION

[0545] The therapeutically effective amount or dose of a composition or medicamentcontaining a GIP receptor agonist peptide of the present disclosure to be administered to a subject will depend on the age, sex and weight of the patient, and the current medical condition 59057274.1of the patient. The skilled artisan will be able to determine appropriate dosages depending on these and other factors to achieve the desired biological response.

[0546] The dosage of the GIP receptor agonist peptide of the present disclosure isappropriately determined according to the subject of administration, symptom, administration method and the like. For example, when the GIP receptor agonist peptide of the present disclosure is administered subcutaneously, intravenously, intramuscularly, intraperitonealy, orally or via inhalation to a subject prior to engaging in an act that will likely cause emesis or after the onset of emesis in a human subject (body weight of approximately 60 kg), the daily dose of the GIP receptor agonist peptide of the present disclosure is about 0.01 to 5,000 mg, or about 1.0 to 500 mg, or about 1.0 to 200 mg. When the compound of the present disclosure is administered parenterally to a subject in need of prevention and / or treatment of emesis, for example, nausea and / or vomiting, (body weight 60 kg), the daily dose of the compound of the present disclosure is about 0.001 to 6,000 mg, or about 0.01 to 2,000 mg, or about 0.1 to 1,000 mg or about 1 to 500 mg. These amounts can be administered in about 1 to several portions a day. In some embodiments, a therapeutically effective amount of a GIP receptor agonist peptide to prevent and / or treat emesis in a subject in need thereof may range from about 0.01 to 0.5 mg / kg / day, 0.1 to 5 mg / kg / day, 5 to 10 mg / kg / day, 10 to 20 mg / kg / day, 20 to 50 mg / kg / day, 10 59057274.1to 100 mg / kg / day, 10 to 120 mg / kg / day, 50 to 100 mg / kg / day, 100 to 200 mg / kg / day, 200 to 300 mg / kg / day, 300 to 400 mg / kg / day, 400 to 500 mg / kg / day, 500 to 600 mg / kg / day, 600 to 700 mg / kg / day, 700 to 800 mg / kg / day, 800 to 900 mg / kg / day or 900 to 1000 mg / kg / day.

[0547] The GIP receptor agonist peptide of the present disclosure can be administered, forexample, once per day, every 2 days, every 3 days, every 4 days, every 5 days, every 6 days, every week, twice per week, every other week, every 3 weeks, every month, every 2 months, every 3 months, every 4 months, every 5 months or every 6 months. In some embodiments, the GIP receptor agonist peptide of the present disclosure can be administered to the subject 1 times per week, QW, or 1-7 times per week, for 1-5 days, 1-5 weeks, 1-5 months, or 1-5 years. In some exemplary embodiments, the GIP receptor agonist peptide or medicament is administered to the subject, 1 time per day, or 1 time per 24 hours, for 1-5 days, 1-5 weeks, 1-5 months, or 1-5 years.

[0548] The GIP receptor agonist peptide of the present disclosure can be used in combinationwith another drug that does not adversely influence the GIP receptor agonist peptide of the present disclosure, for the purpose of, for example, promoting the action (antiemetic action) of the GIP receptor agonist peptide of the present disclosure, reducing the dose of the GIP receptor agonist peptide of the present disclosure, and the like. 59057274.1

[0549] Examples of a drug that can be used in combination with the GIP receptor agonistpeptide of the present disclosure (hereinafter sometimes to be abbreviated as a concomitant drug) include anti-obesity agents, therapeutic agents for diabetes, therapeutic agents for diabetic complications, therapeutic agents for hyperlipidemia, antihypertensive agents, diuretics, chemotherapeutics, immunotherapeutics, anti-inflammatory drugs, antithrombotic agents, therapeutic agents for osteoporosis, vitamins, antidementia drugs, erectile dysfunction drugs, therapeutic drugs for urinary frequency or urinary incontinence, therapeutic agents for dysuria, central D2 receptor antagonists, prokinetic agents, antihistamines, muscarine receptor antagonists, serotonin 5HT3 receptor antagonists, somatostatin analogues, corticosteroids, benzodiazepine anxiolytics, NK-1 receptor antagonists, hypercalcemia therapeutic drug and the like. Specific examples of the concomitant drug include those mentioned below.

[0550] Examples of the anti-obesity agent include monoamine uptake inhibitors (e.g.,phentermine, sibutramine, mazindol, fluoxetine, tesofensine), serotonin 2C receptor agonists (e.g., lorcaserin), serotonin 6 receptor antagonists, histamine H3 receptor modulator, GABA modulator (e.g., topiramate), neuropeptide Y antagonists (e.g., velneperit), cannabinoid receptor antagonists (e.g., rimonabant, taranabant), ghrelin antagonists, ghrelin receptor antagonists, ghrelinacylation enzyme inhibitors, opioid receptor antagonists (e.g., GSK-1521498), orexin 59057274.1receptor antagonists, melanocortin 4 receptor agonists, 11β-hydroxysteroid dehydrogenase inhibitors (e.g., AZD-4017), pancreatic lipase inhibitors (e.g., orlistat, cetilistat), β3 agonists (e.g., N-5984), diacylglycerol acyltransferase 1 (DGAT1) inhibitors, acetylCoA carboxylase (ACC) inhibitors, stearoyl-CoA desaturated enzyme inhibitors, microsomal triglyceride transfer protein inhibitors (e.g., R-256918), Na-glucose cotransporter inhibitors (e.g., JNJ-28431754, remogliflozin), NFκ inhibitory (e.g., HE-3286), PPAR agonists (e.g., GFT-505, DRF-11605), phosphotyrosine phosphatase inhibitors (e.g., sodium vanadate, Trodusquemin), GPR119 agonists (e.g., PSN-821, MBX-2982, APD597), glucokinase activators (e.g., AZD-1656), leptin, leptin derivatives (e.g., metreleptin), CNTF (ciliary neurotrophic factor), BDNF (brain-derived neurotrophic factor), cholecystokinin agonists, amylin preparations (e.g., pramlintide, AC-2307), neuropeptide Y agonists (e.g., PYY3-36, derivatives of PYY3-36, obineptide, TM-30339, TM- 30335), oxyntomodulin preparations: FGF21 preparations (e.g., animal FGF21 preparations extracted from the pancreas of bovine or swine; human FGF21 preparations genetically synthesized using Escherichia coli or yeast; fragments or derivatives of FGF21), anorexigenic agents (e.g., P-57), GLP-1 receptor agonist, GLP-1 receptor / GIP receptor coagonist, glucagon receptor / GLP-1 receptor / GIP receptor triagonist, and the like. 59057274.1

[0551] Here, as the therapeutic agent for diabetes, for example, insulin preparations (e.g.,animal insulin preparations extracted from the pancreas of bovine or swine; human insulin preparations genetically synthesized using Escherichia coli or yeast; zinc insulin; protamine zinc insulin; fragment or derivative of insulin (e.g., INS-1), oral insulin preparation), insulin sensitizers (e.g., pioglitazone or a salt thereof (e.g., hydrochloride), rosiglitazone or a salt thereof (e.g., maleate), Metaglidasen, AMG-131, Balaglitazone, MBX-2044, Rivoglitazone, Aleglitazar, Chiglitazar, Lobeglitazone, PLX-204, PN-2034, GFT-505, THR-0921, compound described in WO007 / 013694, WO2007 / 018314, WO2008 / 093639 or WO2008 / 099794), α-glucosidase inhibitors (e.g., voglibose, acarbose, miglitol, emiglitate), biguanides (e.g., metformin, buformin or a salt thereof (e.g., hydrochloride, fumarate, succinate)), insulin secretagogues (e.g., sulfonylurea (e.g., tolbutamide, glibenclamide, gliclazide, chlorpropamide, tolazamide, acetohexamide, glyclopyramide, glimepiride, glipizide, glybuzole), repaglinide, nateglinide, mitiglinide or calcium salt hydrate thereof), dipeptidyl peptidase IV inhibitors (e.g., Alogliptin or a salt thereof (e.g., benzoate), Vildagliptin, Sitagliptin, Saxagliptin, BI1356, GRC8200, MP-513, PF-00734200, PHX1149, SK-0403, ALS2-0426, TA-6666, TS-021, KRP-104, Trelagliptin or a salt thereof (e.g., succinate)), β3 agonists (e.g., N-5984), GPR40 agonists (e.g., Fasiglifam or a hydrate thereof, compound described in WO2004 / 041266, WO2004 / 106276, WO2005 / 063729, 59057274.1WO2005 / 063725, WO2005 / 087710, WO2005 / 095338, WO2007 / 013689 or WO2008 / 001931), SGLT2 (sodium-glucose cotransporter 2) inhibitors (e.g., Dapagliflozin, AVE2268, TS-033, YM543, TA-7284, Remogliflozin, ASP1941), SGLT1 inhibitors, 11β-hydroxysteroid dehydrogenase inhibitors (e.g., BVT-3498, INCB-13739), adiponectin or agonist thereof, IKK inhibitors (e.g., AS-2868), leptin resistance improving drugs, somatostatin receptor agonists, glucokinase activators (e.g., Piragliatin, AZD1656, AZD6370, TTP-355, compound described in WO2006 / 112549, WO2007 / 028135, WO2008 / 047821, WO2008 / 050821, WO2008 / 136428 or WO2008 / 156757), GPR119 agonists (e.g., PSN821, MBX-2982, APD597), FGF21, FGF analogue, ACC2 inhibitors, GLP-1 receptor agonist, GLP-1 receptor / GIP receptor coagonist, glucagon receptor / GLP-1 receptor / GIP receptor triagonist, and the like can be mentioned.

[0552] As the therapeutic agent for diabetic complications may include, aldose reductaseinhibitors (e.g., tolrestat, epalrestat, zopolrestat, fidarestat, CT-112, ranirestat (AS-3201), lidorestat), neurotrophic factor and increasing agents thereof (e.g., NGF, NT-3, BDNF, neurotrophic production / secretion promoting agent described in WO01 / 14372 (e.g., 4-(4- chlorophenyl)-2-(2-methyl-1-imidazolyl)-5-[3-(2-methylphenoxy)propyl]oxazole), compound described in WO2004 / 039365), PKC inhibitors (e.g., ruboxistaurin mesylate), AGE inhibitors (e.g., ALT946, N-phenacylthiazolium bromide (ALT766), EXO-226, Pyridorin, pyridoxamine), 59057274.1GABA receptor agonists (e.g., gabapentin, pregabalin), serotonin and noradrenalin reuptake inhibitors (e.g., duloxetine), sodium channel inhibitors (e.g., lacosamide), active oxygen scavengers (e.g., thioctic acid), cerebral vasodilators (e.g., tiapuride, mexiletine), somatostatin receptor agonists (e.g., BIM23190), apoptosis signal regulating kinase-1 (ASK-1) inhibitors, GLP-1 receptor agonist, GLP-1 receptor / GIP receptor coagonist, glucagon receptor / GLP-1 receptor / GIP receptor triagonist, and the like can be mentioned.

[0553] As the therapeutic agent for hyperlipidemia, HMG-CoA reductase inhibitors (e.g.,pravastatin, simvastatin, lovastatin, atorvastatin, fluvastatin, rosuvastatin, pitavastatin or a salt thereof (e.g., sodium salt, calcium salt)), squalene synthase inhibitors (e.g., compound described in WO97 / 10224, for example, N-[[(3R,5S)-1-(3-acetoxy-2,2-dimethylpropyl)-7-chloro-5-(2,3- dimethoxyphenyl)-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepin-3-yl]acetyl]piperidin-4-acetic acid), fibrate compounds (e.g., bezafibrate, clofibrate, simfibrate, clinofibrate), anion exchange resin (e.g., colestyramine), probucol, nicotinic acid drugs (e.g., nicomol, niceritrol, niaspan), ethyl icosapentate, phytosterol (e.g., soysterol, gamma oryzanol (γ-oryzanol)), cholesterol absorption inhibitors (e.g., zechia), CETP inhibitors (e.g., dalcetrapib, anacetrapib), ω-3 fatty acid preparations (e.g., ω-3-fatty acid ethyl esters 90 (ω-3-acid ethyl esters 90)) and the like can be mentioned. 59057274.1

[0554] Examples of the antihypertensive agent include angiotensin converting enzymeinhibitors (e.g., captopril, enalapril, delapril, etc.), angiotensin II antagonists (e.g., candesartan cilexetil, candesartan, losartan, losartan potassium, eprosartan, valsartan, telmisartan, irbesartan, tasosartan, olmesartan, olmesartan medoxomil, azilsartan, azilsartan medoxomil, etc.), calcium antagonists (e.g., manidipine, nifedipine, amlodipine, efonidipine, nicardipine, cilnidipine, etc.), β blockers (e.g., metoprolol, atenolol, propranolol, carvedilol, pindolol, etc.), clonidine and the like.

[0555] As the diuretic, for example, xanthine derivatives (e.g., theobromine sodiumsalicylate, theobromine calcium salicylate and the like), thiazide preparations (e.g., ethiazide, cyclopenthiazide, trichloromethiazide, hydrochlorothiazide, hydroflumethiazide, benzylhydrochlorothiazide, penfluthiazide, polythiazide, methyclothiazide and the like), antialdosterone preparations (e.g., spironolactone, triamterene and the like), carbonic anhydrase inhibitors (e.g., acetazolamide and the like), chlorobenzenesulfonamide agents (e.g., chlortalidone, mefruside, indapamide and the like), azosemide, isosorbide, ethacrynic acid, piretanide, bumetanide, furosemide and the like can be mentioned.

[0556] Examples of the chemotherapeutic include alkylating agents (e.g., cyclophosphamide,ifosfamide), antimetabolites (e.g., methotrexate, 5-fluorouracil), anticancer antibiotics (e.g., 59057274.1mitomycin, adriamycin), plant-derived anticancer agents (e.g., vincristine, vindesine, Taxol), cisplatin, carboplatin, etoposide and the like. Among others, a 5-fluorouracil derivative Furtulon or Neofurtulon or the like may be used. Also, a composition comprising a GIP receptor agonist peptide of the disclosure can be administered before, after or during the administration of the following anti-cancer agents: cisplatin, carboplatin. Oxaliplatin, cyclophosphamide, dacarbazine (DTIC), dactinomycin, mechlorethamine (nitrogen mustard), streptozocin, cyclophosphamide, carmustine (BCNU), lomustine (CCNU), doxorubicin (adriamycin), daunorubicin, procarbazine, mitomycin, cytarabine, etoposide, methotrexate, 5-fluorouracil, vinblastine, vincristine, bleomycin, paclitaxel and chlorambucil.

[0557] Examples of the immunotherapeutic include microbial or bacterial components (e.g.,muramyl dipeptide derivative, Picibanil), polysaccharides having immunoenhancing activity (e.g., lentinan, sizofiran, Krestin), cytokines obtained by genetic engineering approaches (e.g., interferon, interleukin (IL)), colony-stimulating factors (e.g., granulocyte colony-stimulating factor, erythropoietin) and the like. Among others, interleukins such as IL-1, IL-2, IL-12 and the like are some examples.

[0558] Examples of the anti-inflammatory drug include nonsteroidal anti-inflammatory drugssuch as aspirin, acetaminophen, indomethacin and the like. 59057274.1

[0559] As the antithrombotic agent, for example, heparin (e.g., heparin sodium, heparincalcium, enoxaparin sodium, dalteparin sodium), warfarin (e.g., warfarin potassium), anti- thrombin drugs (e.g., aragatroban, dabigatran), FXa inhibitors (e.g., rivaroxaban, apixaban, edoxaban, YM150, compound described in WO2002 / 06234, WO2004 / 048363, WO2005 / 030740, WO2005 / 058823 or WO2005 / 113504), thrombolytic agents (e.g., urokinase, tisokinase, alteplase, nateplase, monteplase, pamiteplase), platelet aggregation inhibitors (e.g., ticlopidine hydrochloride, clopidogrel, prasugrel, E5555, SHC530348, cilostazol, ethyl icosapentate, beraprost sodium, sarpogrelate hydrochloride) and the like can be mentioned.

[0560] Examples of the therapeutic agent for osteoporosis include alfacalcidol, calcitriol,elcatonin, calcitonin salmon, estriol, ipriflavone, pamidronate disodium, alendronate sodium hydrate, incadronate disodium, risedronate disodium and the like.

[0561] Examples of the vitamin include vitamin B1, vitamin B12 and the like.

[0562] Examples of the antidementia drug include tacrine, donepezil, rivastigmine,galanthamine and the like.

[0563] Examples of the erectile dysfunction drug include apomorphine, sildenafil citrate andthe like. 59057274.1

[0564] Examples of the therapeutic drug for urinary frequency or urinary incontinenceinclude flavoxate hydrochloride, oxybutynin hydrochloride, propiverine hydrochloride and the like.

[0565] Examples of the therapeutic agent for dysuria include acetylcholine esterase inhibitors(e.g., distigmine) and the like.

[0566] Examples of the central D2 receptor antagonist include typical psychotropic drugs(prochlorperazine, haloperidol, chlorpromazine, and the like), serotonin dopamine antagonists (perospirone, risperidone, and the like), and multi-acting receptor targeted antipsychotic drugs (olanzapine and the like).

[0567] Examples of the prokinetic agent include peripheral D2 receptor antagonists(metoclopramide, domperidone, and the like) and 5HT4 receptor agonists (mosapride and the like).

[0568] Examples of the antihistamine include hydroxyzine, diphenhydramine, andchlorpheniramine.

[0569] Examples of the muscarinic receptor antagonist include central muscarinic receptorantagonists (scopolamine and the like) and peripheral muscarinic receptor antagonists (butylscopolamine and the like). 59057274.1

[0570] Examples of the serotonin 5HT3 receptor antagonist include granisetron,ondansetron, azasetron, indisetron, palonosetron, and ramosetron.

[0571] Examples of the somatostatin analogue include octreotide.

[0572] Examples of the corticosteroid include dexamethasone, betamethasone, andmethylprednisolone.

[0573] Examples of the benzodiazepine anxiolytic include lorazepam and alprazolam,examples of the NK-1 receptor antagonist include aprepitant and fosaprepitant, and examples of the hypercalcemia therapeutic drug include bisphosphonate.

[0574] Moreover, a drug confirmed to have a cachexia-ameliorating action either in animalmodels or clinically, i.e., a cyclooxygenase inhibitor (e.g., indomethacin), a progesterone derivative (e.g., megestrol acetate), glucocorticoid (e.g., dexamethasone), a metoclopramide drug, a tetrahydrocannabinol drug, an agent for improving fat metabolism (e.g., eicosapentaenoic acid), growth hormone, IGF-1, or an antibody against a cachexia-inducing factor TNF-α, LIF, IL-6 or oncostatin M or the like can also be used in combination with the compound of the present disclosure.

[0575] Alternatively, a glycation inhibitor (e.g., ALT-711), a nerve regeneration-promotingdrug (e.g., Y-128, VX853, prosaptide), an antidepressant (e.g., desipramine, amitriptyline, 59057274.1imipramine), an antiepileptic drug (e.g., lamotrigine, Trileptal, Keppra, Zonegran, Pregabalin, Harkoseride, carbamazepine), an antiarrhythmic drug (e.g., mexiletine), an acetylcholine receptor ligand (e.g., ABT-594), an endothelin receptor antagonist (e.g., ABT-627), a monoamine uptake inhibitor (e.g., tramadol), a narcotic analgesic (e.g., morphine), a GABA receptor agonist (e.g., gabapentin, MR preparation of gabapentin), an α2 receptor agonist (e.g., clonidine), a local analgesic (e.g., capsaicin), an antianxiety drug (e.g., benzothiazepine), a phosphodiesterase inhibitor (e.g., sildenafil), a dopamine receptor agonist (e.g., apomorphine), midazolam, ketoconazole or the like may be used in combination with the compound of the present disclosure.

[0576] The time of administration of the GIP receptor agonist peptide of the presentdisclosure and that of the concomitant drug are not limited, and they may be administered simultaneously or in a staggered manner to the administration subject.

[0577] Examples of such administration mode include the following:

[0578] (1) administration of a single preparation obtained by simultaneously processing theGIP receptor agonist peptide of the present disclosure and the concomitant drug, (2) simultaneous administration of two kinds of preparations of the GIP receptor agonist peptide of the present disclosure and the concomitant drug, which have been separately produced, by the 59057274.1same administration route, (3) administration of two kinds of preparations of the GIP receptor agonist peptide of the present disclosure and the concomitant drug, which have been separately produced, by the same administration route in a staggered manner, (4) simultaneous administration of two kinds of preparations of the GIP receptor agonist peptide of the present disclosure and the concomitant drug, which have been separately produced, by different administration routes, (5) administration of two kinds of preparations of the compound of the present disclosure and the concomitant drug, which have been separately produced, by different administration routes in a staggered manner (e.g., administration in the order of the GIP receptor agonist peptide of the present disclosure and the concomitant drug, or in the reverse order) and the like.

[0579] The dose of the concomitant drug can be appropriately determined based on the doseemployed in clinical situations. The mixing ratio of the GIP receptor agonist peptide of the present disclosure and a concomitant drug can be appropriately determined depending on the administration subject, symptom, administration method, target disease, combination and the like. When the subject of administration is human, for example, a concomitant drug can be used in 0.01 - 100 parts by weight relative to 1 part by weight of the GIP receptor agonist peptide of the present disclosure. 59057274.1

[0580] By combining the GIP receptor agonist peptide of the present disclosure andconcomitant drug: (1) the dose of the GIP receptor agonist peptide of the present disclosure or a concomitant drug can be reduced as compared to single administration of the GIP receptor agonist peptide of the present disclosure or a concomitant drug,

[0581] (2) the drug to be used in combination with the GIP receptor agonist peptide of thepresent disclosure can be selected depending on the condition of patients (mild, severe and the like),

[0582] (3) the period of treatment can be set longer by selecting a concomitant drug havingdifferent action and mechanism from those of the GIP receptor agonist peptide of the present disclosure,

[0583] (4) a sustained treatment effect can be designed by selecting a concomitant drughaving different action and mechanism from those of the GIP receptor agonist peptide of the present disclosure, and

[0584] (5) a synergistic effect can be afforded by a combined use of the GIP receptor agonistpeptide of the present disclosure and a concomitant drug, and the like, can be achieved.

[0585] All publications, patents, and patent applications cited herein are incorporated herein byreference in their entirety. 59057274.1

[0586] F. EXAMPLES

[0587] The abbreviations used in the present specification mean the following (Table 1). Ahyphen in terms such as α-MePhe and the like as described herein may be omitted, and the event of omission also represents the same meaning.

[0588] In the amino acid sequences used in the present specification, the left terminalrepresents N terminal and the right terminal represents C terminal.

[0589] Table 1. Commonly Used Abbreviations in the Present Disclosure.Ac acetyl Aib α-aminoisobutyric acid Ambz(4) 4-aminomethylbenzoyl GABA γ--aminobutyric acid Iva isovaline Lys(Ac) Nε-acetyllysine α-MePhe α-methylphenylalanine MeTyr N-Methyltyrosine Hda Doda Trda Teda Peda Heda Hepda 59057274.1Oda Eda Dda Pal PEG (2) PEG3 (PEG3) 2 (PEG3) 3 (PEG3) 4 (PEG3) 5 PEG (4) γGlu (γGlu) 2 (γGlu) 3 (γGlu) 2- PEG3 AMBZ -PEG3 GABA- (PEG3) 2 GABA-GGG GG 59057274.1GGG GGGG GGGGG or G5 GGGGGG G9 NpipAc NpipAc- PEG3 Tra Tra-GGG Tra-PEG3 γGlu-PEG3 γGlu- (PEG3)2 γGlu-AMBZ- PEG3 γGlu-GGG εLys εLys-GGG εLys-PEG3 gE 59057274.1OEG = AEEA = PEG3 GGGGG or G5 GGEEE = G2E3 G3gEgE 2OEGgEgE OEGgEgE GGPAPAP 2OEGgE 59057274.13OEGgEgE G4gE G5gE 2OEGgEgEgE 2OEG G5gEgE gE = γGlu C17DA = C17 diacid C18DA = C18 diacid C18 C20DA = C20 diacid Ac Me-Tyr = MeTyr 59057274.1Aib PEG linkers used for Cys. PEG = 5 – 30 kDa PEGthey arebased on conventional codes in accordance with the IUPAC-IUB Commission on Biochemical Nomenclature or by the common codes in the art, examples of which are shown below. For amino acids that may have an optical isomer, L-form is presented unless otherwise indicated (e.g., “Ala” is L-form of Ala). In addition, “D-” means a D-form (e.g., “D-Ala” is D-form of Ala), and “DL-” means a racemate of a D-form and an L-form (e.g., “DL-Ala” is DL racemate of Ala).

[00591] The present disclosure is explained in detail in the following by referring to thefollowing Reference Examples, Examples, Test Examples and Formulation Examples, which are mere embodiments and not to be construed as limitative. In addition, the present disclosure may be modified without departing from the claimed scope. 59057274.1

[0592] The term “room temperature” in the following Examples indicates the range ofgenerally from about 10°C to about 35°C. As for “%”, the yield is in mol / mol%, the solvent used for chromatography is in % by volumeis in % by weight.

[0593] Solvents can include protic or aprotic organic solvents. Exemplary solvents caninclude: NMP: methylpyrrolidone THF: tetrahydrofuran DMF: N,N-dimethylformamide WSC: 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride DCC: N,N’-Dicyclohexylcarbodiimide DIPCDI: N,N’-diisopropylcarbodiimide HOBt: 1-hydroxybenzotriazole monohydrate Oxyma: ethyl 2-cyano-2-(hydroxyimino)acetate

[0594] Example 1. Synthesis Schemes

[0595] Exemplary methods for synthesizing GIP receptor agonist peptides are disclosed forexample in Applicant’s International PCT Application No. PCT / JP2018 / 013540, filed on March 59057274.130, 2018, ranging from pages 162 to 213, the disclosure of which is specifically incorporated herein by reference in its entirety.

[0596] Example 2. Synthesis of Selective GIP Receptor Agonist Peptides of the PresentDisclosure. Compound A; SEQ ID NO 2. Peptide Synthesis: The peptide was synthesized using standard Fmoc chemistry.1) Resin preparation: The 9H-fluoren-9-ylmethyl N-[(2,4-dimethoxyphenyl)-[4-[2-oxo-2-[[phenyl(p-tolyl)methyl]amino]ethoxy]phenyl]methyl]carbamate (0.60 mmol, 1.00 eq) in DMF (20 mL) was agitated with N2for 1 h at 25°C.2) Deprotection: 20% piperidine in DMF (20.0 mL) was added and agitated the resin with N2 at25 °C for 15 min. The resin was washed with DMF (20.0 mL * 6) and filtered to get the resin.3) Coupling: A solution of HBTU (2.85 eq) and Fmoc-Ser(tBu)-OH (3.00 eq) in DMF (10.0 mL)was added to the resin, then the DIEA (6.00 eq) was added, the mixture was agitated with N2 at 25 ℃ for 30 min. The resin was washed with DMF (20.0 mL * 6).4) Repeated above step 2 to 3 for the coupling of following amino acids: (1-39)# Materials Coupling reagents 59057274.11Fmoc-Pro-OH (3.00 eq)HBTU (2.85 eq) and DIEA (6.00 eq)2Fmoc-Pro-OH (3.00 eq)HBTU (2.85 eq) and DIEA (6.00 eq)3Fmoc-Pro-OH (3.00 eq)HBTU (2.85 eq) and DIEA (6.00 eq)4Fmoc-Ala-OH (3.00 eq)HBTU (2.85 eq) and DIEA (6.00 eq)5Fmoc-Gly-OH (3.00 eq)HBTU (2.85 eq) and DIEA (6.00 eq)6Fmoc-Ser(tBu)-OH (3.00 eq)HBTU (2.85 eq) and DIEA (6.00 eq)7Fmoc-Ser(tBu)-OH (3.00 eq)HBTU (2.85 eq) and DIEA (6.00 eq)8Fmoc-Pro-OH (3.00 eq)HBTU (2.85 eq) and DIEA (6.00 eq)9Fmoc-Lys(Dde)-OH (1.50 eq)HATU (1.43 eq) and DIEA (6.00 eq)10Fmoc-Gln(Trt)-OH (3.00 eq)HBTU (2.85 eq) and DIEA (6.00 eq)11 Fmoc-Ala-OH (3.00 eq)HBTU (2.85 eq) and DIEA (6.00 eq)12Fmoc-Leu-OH (3.00 eq)HBTU (2.85 eq) and DIEA (6.00 eq)13Fmoc-Leu-OH (3.00 eq)HBTU (2.85 eq) and DIEA (6.00 eq)14 Fmoc-Trp(Boc)-OH (3.00 eq)HBTU (2.85 eq) and DIEA (6.00 eq)15Fmoc-Asn(Trt)-OH (3.00 eq)HBTU (2.85 eq) and DIEA (6.00 eq)16 Fmoc-Val-OH (3.00 eq)HBTU (2.85 eq) and DIEA (6.00 eq)17Fmoc-Phe-OH (3.00 eq)HBTU (2.85 eq) and DIEA (6.00 eq)18Fmoc-Asp(OtBu)-OH (3.00 eq)HBTU (2.85 eq) and DIEA (6.00 eq)19 Fmoc-Aib-OH (3.00 eq)HBTU (2.85 eq) and DIEA (6.00 eq)20 Fmoc-Gln(Trt)-OH (3.00 eq)HATU (2.85 eq) and DIEA (6.00 eq)21 Fmoc-Ala-OH (3.00 eq)HBTU (2.85 eq) and DIEA (6.00 eq)59057274.122 Fmoc-Glu(OtBu)-OH (3.00 eq)HBTU (2.85 eq) and DIEA (6.00 eq)23 Fmoc-Arg(Pbf)-OH (3.00 eq)HBTU (2.85 eq) and DIEA (6.00 eq)24 Fmoc-Asp(OtBu)-OH (3.00 eq)HBTU (2.85 eq) and DIEA (6.00 eq)25 Fmoc-Leu-OH (3.00 eq)HBTU (2.85 eq) and DIEA (6.00 eq)26 Fmoc-Aib-OH (3.00 eq)HBTU (2.85 eq) and DIEA (6.00 eq)27 Fmoc-Ile -OH (9.00 eq)HOAT (9.00 eq) and DIC (9.00 eq)28 Fmoc-Ser(tBu)-OH (3.00 eq)HBTU (2.85 eq) and DIEA (6.00 eq)29 Fmoc-Tyr(tBu)-OH (3.00 eq)HBTU (2.85 eq) and DIEA (6.00 eq)30 Fmoc-Leu-OH (3.00 eq)HATU (2.85 eq) and DIEA (6.00 eq)31 Fmoc-Ser(tBu)-OH (3.00 eq)HATU (2.85 eq) and DIEA (6.00 eq)32 Fmoc-Val-OH (3.00 eq)HATU (2.85 eq) and DIEA (6.00 eq)33 Fmoc-Val-OH (3.00 eq)HATU (2.85 eq) and DIEA (6.00 eq)34 Fmoc-Thr(tBu)-OH (3.00 eq)HATU (2.85 eq) and DIEA (6.00 eq)35 Fmoc-Gly-OH (3.00 eq)HATU (2.85 eq) and DIEA (6.00 eq)36 Fmoc-Glu(OtBu)-OH (3.00 eq)HATU (2.85 eq) and DIEA (6.00 eq)37Fmoc-Aib-OH (3.00 eq)HATU (2.85 eq) and DIEA (6.00 eq)38Fmoc-NME-Tyr(tBu)-OH (3.00 eq)HOAT (3.00 eq) and DIC (3.00 eq)39Boc2O (6.00 eq)DIEA (3.00 eq)5) After the coupling of Boc2O, add 3% H2N·NH2 / DMF (20.0 mL) and reacted on 10 min andthen repeated it for one more time. Drained and washed with DMF (20.0 mL) for 6 times. 59057274.16) Repeated above step 2 to 3 for the coupling of following amino acids: (40-43).Note: 40 Fmoc-AEEA-OH (3.00 eq)HATU (2.85 eq) and DIEA (6.00 eq)41 Fmoc-AEEA-OH (3.00 eq)HATU (2.85 eq) and DIEA (6.00 eq)42 Fmoc-Glu-OtBu (3.00 eq)HATU (2.85 eq) and DIEA (6.00 eq)43C18Diacid(tBu) (3.00 eq) HATU (2.85 eq) and DIEA (6.00 eq) Peptide Cleavage and Purification:1) Added cleavage solution (40 mL, 92.5% TFA / 2.5% H2O / 5.0% 3-Mercaptopropionic acid) tothe flask containing resin at room temperature and stirred for 2 h.2) The peptide was precipitated with cold isopropyl ether (250 mL) and centrifuged (2 min at5000 rpm) and washed two times with isopropyl ether. The crude peptide was dried under vacuum to get 2.5 g crude peptide.3) The crude peptide was purified by prep-HPLC (TFA condition: A: 0.075 % TFA in H2O, B:ACN) and then by prep-HPLC (HOAc condition; 30℃, A:0.5% HOAc / H2O, B:ACN; ) to give the final product Compound A; SEQ ID NO 2 (298.7 mg, 60.7 μmol, 10.1% yield, 97.13% purity, HOAC) as a white solid, which was confirmed by LCMS (Rt=1.808 min) and HPLC (Rt=11.310 min). 59057274.1Purification conditions 1: First separation condition Dissolution condition Dissolve in 35% ACN-H2O Instrument Gilson GX-281 A: H2O (0.075% TFA in H2O) Mobile Phase B: CH3CN Gradient 28-48-50 min , Retention time: 25 min Column luna ,10um, c18,100A,25mm+Gemin,5um,c18,110A Flow Rate 20 mL / Min Wavelength 220 / 254 nm Oven Tem. 30oC

[0597] Example 3. Synthesis of Selective GIP Receptor Agonist Peptides of thePresent Disclosure. Compound No. C; SEQ ID NO: 3. Peptide Synthesis: The peptide was synthesized using standard Fmoc chemistry.1) Resin preparation: The 9H-fluoren-9-ylmethyl N-[(2,4-dimethoxyphenyl)-[4-[2-oxo-2-[[phenyl(p-tolyl)methyl]amino]ethoxy]phenyl]methyl]carbamate (0.60 mmol, 1.00 eq) in DMF (20 mL) was agitated with N2 for 1 h at 25°C. 59057274.12) Deprotection: 20% piperidine in DMF (20.0 mL) was added and agitated the resin with N2 at25 °C for 15 min. The resin was washed with DMF (20.0 mL * 6) and filtered to get the resin.3) Coupling: A solution of HBTU (2.85 eq) and Fmoc-Ser(tBu)-OH (3.00 eq) in DMF (10.0 mL)was added to the resin, then the DIEA (6.00 eq) was added, the mixture was agitated with N2at 25 ℃ for 30 min. The resin was washed with DMF (20.0 mL * 6).4) Repeated above step 2 to 3 for the coupling of following amino acids: (1-39)# Materials Coupling reagents 1Fmoc-Pro-OH (3.00 eq)HBTU (2.85 eq) and DIEA (6.00 eq)2Fmoc-Pro-OH (3.00 eq)HBTU (2.85 eq) and DIEA (6.00 eq)3Fmoc-Pro-OH (3.00 eq)HBTU (2.85 eq) and DIEA (6.00 eq)4Fmoc-Ala-OH (3.00 eq)HBTU (2.85 eq) and DIEA (6.00 eq)5Fmoc-Gly-OH (3.00 eq)HBTU (2.85 eq) and DIEA (6.00 eq)6Fmoc-Ser(tBu)-OH (3.00 eq)HBTU (2.85 eq) and DIEA (6.00 eq)7Fmoc-Ser(tBu)-OH (3.00 eq)HBTU (2.85 eq) and DIEA (6.00 eq)8Fmoc-Pro-OH (3.00 eq)HBTU (2.85 eq) and DIEA (6.00 eq)9Fmoc-Arg(Pbf)-OH (3.00 eq)HBTU (2.85 eq) and DIEA (6.00 eq)10Fmoc-Gln(Trt)-OH (3.00 eq)HBTU (2.85 eq) and DIEA (6.00 eq)11 Fmoc-Ala-OH (3.00 eq)HBTU (2.85 eq) and DIEA (6.00 eq)12Fmoc-Leu-OH (3.00 eq)HBTU (2.85 eq) and DIEA (6.00 eq)59057274.113Fmoc-Leu-OH (3.00 eq)HBTU (2.85 eq) and DIEA (6.00 eq)14 Fmoc-Trp(Boc)-OH (3.00 eq)HBTU (2.85 eq) and DIEA (6.00 eq)15Fmoc-Lys(Dde)-OH (1.50 eq)HATU (1.43 eq) and DIEA (6.00 eq)16Fmoc-Val-OH (3.00 eq)HBTU (2.85 eq) and DIEA (6.00 eq)17 Fmoc-Phe-OH (3.00 eq)HBTU (2.85 eq) and DIEA (6.00 eq)18Fmoc-Asp(OtBu)-OH (3.00 eq)HBTU (2.85 eq) and DIEA (6.00 eq)19 Fmoc-Aib-OH (3.00 eq)HBTU (2.85 eq) and DIEA (6.00 eq)20 Fmoc-Gln(Trt)-OH (3.00 eq)HATU (2.85 eq) and DIEA (6.00 eq)21 Fmoc-Ala-OH (3.00 eq)HBTU (2.85 eq) and DIEA (6.00 eq)22 Fmoc-Glu(OtBu)-OH (3.00 eq)HBTU (2.85 eq) and DIEA (6.00 eq)23 Fmoc-Arg(Pbf)-OH (3.00 eq)HBTU (2.85 eq) and DIEA (6.00 eq)24 Fmoc-Asp(OtBu)-OH (3.00 eq)HBTU (2.85 eq) and DIEA (6.00 eq)25 Fmoc-Leu-OH (3.00 eq)HBTU (2.85 eq) and DIEA (6.00 eq)26 Fmoc-Aib-OH (3.00 eq)HBTU (2.85 eq) and DIEA (6.00 eq)27 Fmoc-Ile -OH (9.00 eq)HOAT (9.00 eq) and DIC (9.00 eq)28 Fmoc-Ser(tBu)-OH (3.00 eq)HBTU (2.85 eq) and DIEA (6.00 eq)29 Fmoc-Tyr(tBu)-OH (3.00 eq)HBTU (2.85 eq) and DIEA (6.00 eq)30 Fmoc-Leu-OH (3.00 eq)HATU (2.85 eq) and DIEA (6.00 eq)31 Fmoc-Ser(tBu)-OH (3.00 eq)HATU (2.85 eq) and DIEA (6.00 eq)32 Fmoc-Val-OH (3.00 eq)HATU (2.85 eq) and DIEA (6.00 eq)33 Fmoc-Val-OH (3.00 eq)HATU (2.85 eq) and DIEA (6.00 eq)59057274.134 Fmoc-Thr(tBu)-OH (3.00 eq)HATU (2.85 eq) and DIEA (6.00 eq)35 Fmoc-Gly-OH (3.00 eq)HATU (2.85 eq) and DIEA (6.00 eq)36 Fmoc-Glu(OtBu)-OH (3.00 eq)HATU (2.85 eq) and DIEA (6.00 eq)37Fmoc-Aib-OH (3.00 eq)HATU (2.85 eq) and DIEA (6.00 eq)38Fmoc-NME-Tyr(tBu)-OH (3.00 eq)HOAT (3.00 eq) and DIC (3.00 eq)39Boc2O (6.00 eq)DIEA (3.00 eq)5) After the coupling of Boc2O, add 3% H2N·NH2 / DMF (20.0 mL) and reacted on 10 min andthen repeated it for one more time. Drain and wash with DMF (20.0 mL) for 6 times.6) Repeated above step 2 to 3 for the coupling of following amino acids: (40-43).40 Fmoc-AEEA-OH (3.00 eq)HATU (2.85 eq) and DIEA (6.00 eq)41 Fmoc-AEEA-OH (3.00 eq)HATU (2.85 eq) and DIEA (6.00 eq)42 Fmoc-Glu-OtBu (3.00 eq)HATU (2.85 eq) and DIEA (6.00 eq)43C18Diacid(tBu) (3.00 eq) HATU (2.85 eq) and DIEA (6.00 eq) Peptide Cleavage and Purification:4) Added cleavage solution (40 mL, 92.5% TFA / 2.5% H2O / 5.0% 3-Mercaptopropionic acid) tothe flask containing resin at room temperature and stirred for 2 h.5) The peptide was precipitated with cold isopropyl ether (250 mL) and centrifuged (2 min at5000 rpm) and washed two times with isopropyl ether. The crude peptide was dried under vacuum to get 2.5 g crude peptide. 59057274.16) The crude peptide was purified by prep-HPLC (TFA condition: A: 0.075 % TFA in H2O, B:ACN) and then by prep-HPLC (HOAc condition; 30℃, A:0.5% HOAc / H2O, B:ACN; ) to give the final product (307.7 mg, 62.0 μmol, 10.3% yield, 96.41% purity, HOAC) as a white solid, which was confirmed by LCMS (Rt=1.783 min) and HPLC (Rt=9.409 min). Purification conditions 1: First separation condition Dissolution condition Dissolve in 35% ACN-H2O Instrument Gilson GX-281 A: H2O (0.075% TFA in H2O) Mobile Phase B: CH3CN Gradient 31-51-50 min , Retention time: 25 min Column luna ,10um, c18,100A,25mm+Gemin,5um,c18,110A Flow Rate 20 mL / Min Wavelength 220 / 254 nm Oven Tem. 30oC Second separation condition Dissolution Dissolve in 35% ACN-H2O condition 59057274.1Instrument Gilson GX-281 A: H2O (0.5% HOAc in H2O) Mobile Phase B: CH3CN 0.2M NH4Ac 25 min, 0.5% HOAc 10min, 26-56-50 min, Retention Gradient time: 64 min Column luna ,10um, c18,100A,25mm+Gemin,5um,c18,110A Flow Rate 20 mL / Min Wavelength 220 / 254 nm Oven Tem. 30oC Purification conditions 2: LCMS: EW14391-93-P21A, Rt= 1.808 min HPLC: EW14391-93-P21B, Rt= 11.310 min, purity: 97.13%

[0598] Example 4. Synthesis of Selective GIP Receptor Agonist Peptides of the PresentDisclosure. Compound No. D; SEQ ID NO: 5. Peptide Synthesis: The peptide was synthesized using standard Fmoc chemistry.1. Resin preparation: The Rink Amine MBHA resin (25.0 mmol, 1.0 eq, 75.8 g, Sub 0.33mmol / g) in DMF (750 mL) was agitated with N2 for 2 hrs at 20°C. Then 20% piperidine in DMF (1.5 L) was added and the mixture was agitated with N2 for 15 min at 20°C. Then the 59057274.1mixture was filtered to get the resin. The resin was washed with DMF (1.5 L*6) and filtered to get the resin.2. Coupling: a solution of FMOC-SER(TBU)-OH (3.00 eq) and HBTU (2.85 eq), DIEA (6.00eq) in DMF (750 mL) was added to the resin and agitated with N2for 30 min at 20°C. The resin was then washed with DMF (1.5 L*6).3. Deprotection: 20% piperidine in DMF (1.5 L) was added to the resin and the mixture wasagitated with N2 for 15 min at 20°C. The resin was washed with DMF (1.5 L*6) and filtered to get the resin.4. Repeat step 2 to 3 for the coupling of following amino acids: (1-38)# Materials Coupling reagents1 FMOC-PRO-OH (3.00 eq) HBTU (2.85 eq) and DIEA (6.00 eq)2 FMOC-PRO-OH (3.00 eq) HBTU (2.85 eq) and DIEA (6.00 eq)3 FMOC-PRO-OH (3.00 eq) HBTU (2.85 eq) and DIEA (6.00 eq)4 FMOC-ALA-OH (3.00 eq) HBTU (2.85 eq) and DIEA (6.00 eq)5 FMOC-GLY-OH (3.00 eq) HBTU (2.85 eq) and DIEA (6.00 eq)6 FMOC-SER(TBU)-OH (3.00 eq) HBTU (2.85 eq) and DIEA (6.00 eq)7 FMOC-SER(TBU)-OH (3.00 eq) HBTU (2.85 eq) and DIEA (6.00 eq)8 FMOC-PRO-OH (3.00 eq) HBTU (2.85 eq) and DIEA (6.00 eq)9 FMOC-ARG(PBF)-OH (3.00 eq) HBTU (2.85 eq) and DIEA (6.00 eq)10 FMOC-GLN(TRT)-OH (3.00 eq) HBTU (2.85 eq) and DIEA (6.00 eq)11 FMOC-ALA-OH (3.00 eq) HBTU (2.85 eq) and DIEA (6.00 eq)12 FMOC-LEU-OH (3.00 eq) HBTU (2.85 eq) and DIEA (6.00 eq)13 FMOC-LEU-OH (3.00 eq) HBTU (2.85 eq) and DIEA (6.00 eq)14 FMOC-TRP(BOC)-OH (3.00 eq) HBTU (2.85 eq) and DIEA (6.00 eq)59057274.115 FMOC-LYS(DDE)-OH (3.00 eq) HBTU (2.85 eq) and DIEA (6.00 eq)16 FMOC-VAL-OH (3.00 eq) HBTU (2.85 eq) and DIEA (6.00 eq)17 FMOC-PHE-OH (3.00 eq) HBTU (2.85 eq) and DIEA (6.00 eq)18 FMOC-GLU(OTBU)-OH (3.00 eq) HBTU (2.85 eq) and DIEA (6.00 eq)19 FMOC-AIB-OH (3.00 eq) HBTU (2.85 eq) and DIEA (6.00 eq)20 FMOC-GLN(TRT)-OH (3.00 eq) HATU (2.85 eq) and DIEA (6.00 eq)21 FMOC-ALA-OH (3.00 eq) HBTU (2.85 eq) and DIEA (6.00 eq)22 FMOC-GLN(TRT)-OH (3.00 eq) HBTU (2.85 eq) and DIEA (6.00 eq)23 FMOC-ARG(PBF)-OH (3.00 eq) HBTU (2.85 eq) and DIEA (6.00 eq)24 FMOC-ASP(OTBU)-OH (3.00 eq) HBTU (2.85 eq) and DIEA (6.00 eq)25 FMOC-LEU-OH (3.00 eq) HBTU (2.85 eq) and DIEA (6.00 eq)26 FMOC-AIB-OH (3.00 eq) HBTU (2.85 eq) and DIEA (6.00 eq)27 FMOC-ILE-OH (6.00 eq) HATU (5.70 eq) and DIEA (12.0 eq)28 FMOC-SER(TBU)-OH (3.00 eq) HBTU (2.85 eq) and DIEA (6.00 eq)29 FMOC-TYR(TBU)-OH (3.00 eq) HBTU (2.85 eq) and DIEA (6.00 eq)30 FMOC-LEU-OH (3.00 eq) HBTU (2.85 eq) and DIEA (6.00 eq)31 FMOC-SER(TBU)-OH (3.00 eq) HBTU (2.85 eq) and DIEA (6.00 eq)32 FMOC-VAL-OH (3.00 eq) HBTU (2.85 eq) and DIEA (6.00 eq)33 FMOC-VAL-OH (3.00 eq) HATU (2.85 eq) and DIEA (6.00 eq)34 FMOC-THR(TBU)-OH (3.00 eq) HATU (2.85 eq) and DIEA (6.00 eq)35 FMOC-GLY-OH (3.00 eq) HATU (2.85 eq) and DIEA (6.00 eq)36 FMOC-GLU(OTBU)-OH (3.00 eq) HATU (2.85 eq) and DIEA (6.00 eq)37 FMOC-AIB-OH (3.00 eq) HATU (2.85 eq) and DIEA (6.00 eq)38 BOC-TYR(TBU)-OH (3.00 eq) HATU (2.85 eq) and DIEA (6.00 eq)5. Add 3% N2H4▪H2O / DMF (1.5 L) and react on 20 min and then repeat it for one more time.Drain and wash with DMF (1.5 L*6).6. Repeat step 2 to 3 for the coupling of following amino acids: (1-4)# Materials Coupling reagents59057274.11 FMOC-AEEA-OH (3.00 eq) HBTU (2.85 eq) and DIEA (6.00 eq)2 FMOC-AEEA-OH (3.00 eq) HBTU (2.85 eq) and DIEA (6.00 eq)3 FMOC-GLU-OTBU (3.00 eq) HBTU (2.85 eq) and DIEA (6.00 eq)4 FMOC-GLU-OTBU (3.00 eq) HBTU (2.85 eq) and DIEA (6.00 eq)7. Coupling: A solution of 14-(tert-butoxy)-14-oxotetradecanoic acid (2.00 eq) and DIEA (4.00eq), HBTU (1.90 eq) in DMF (750 mL) was added to the resin and agitated with N2for 1hr at 20°C. The resin was then washed with DMF (1.5 L*6).8. The coupling reaction was monitored by ninhydrin color reaction and LCMS showed thedesired mass was detected. Peptide Cleavage and Purification:9. After coupling, the resin was washed with DMF for 5 times. After last step, the resin waswashed with MeOH for 3 times, and dried under vacuum. Then the peptide resin (251 g) was treated with the cleavage cocktail (2.5 L, 92.5% TFA / 2.5% 3-Mercaptopropionic acid / 2.5% TIS / 2.5% H2O) for 2.0 hours. The peptide was concentrated under reduced pressure and precipitated with cold isopropyl ether, filtered and washed two times with isopropyl ether to give 130 g residue.10. The crude peptide was purified by Prep-HPLC (A: 0.075% TFA in H2O, B: ACN) and thenwas second purified by Prep-HPLC (A: 0.5% HOAc in H2O, B: ACN) to give the Compound 59057274.1138 (14.52 g, 98.61% purity, HOAC) was obtained as a white solid, which was confirmed by LCMS (Rt =1.761 min) and HPLC (Rt =10.739 min). Purification Conditions: First Purification condition Dissolution condition Dissolve in 20% ACN in H2OInstrument Gilson GX-281 A: H2O (0.075% TFA in H2O) Mobile Phase B: ACN Gradient 27-47-50 min. Retention time: 35 min Column Gemini, 5um, C18, 110A+luna, C18, 10um, 100A Flow Rate 20 mL / Min Wavelength 214 / 254 nm Oven Tem. 30oC Second Purification condition Dissolution condition Dissolve in 30% ACN in H2OInstrument Gilson GX-281 A: H2O (0.5% HOAc in H2O) Mobile Phase B: ACN 59057274.1Gradient 0.4M NH4Ac 25 min, 0.5% HOAc 10min, 24-54 -50 min. Retention time: 70 min Column luna, C18, 10um, 100A Flow Rate 20 mL / Min Wavelength 214 / 254 nm Oven Tem. 30oC

[00599] Table 2 below lists exemplary GIP receptor agonist peptides made according tomethods described in Examples 1-4. 59057274.12elbaT 59057274.1Biological Examples

[0600] Methods for performing GIP and GLP functional (e.g., receptor binding) assays, assaysfor inhibition of emesis, vomiting and nausea, caused by various stimuli, including from drug or chemotherapy induced emesis are specifically described in Applicant’s International PCT Application No. PCT / JP2018 / 013540, filed on March 30, 2018, ranging from pages 213 to 255, and are specifically incorporated herein by reference in their entirety.

[0601] Example 5 - Evaluation of Peptide Agonist Activity on Human GIPR and HumanGLP1R by Measuring Intracellular cAMP Accumulation

[0602] GIPR Assay

[0603] CHO-K1 cells stably overexpressing low levels of full-length human GIPR with asequence identical to GenBank accession number NM_000164 with an N-terminal FLAG tag were purchased from Multispan, Inc (Hayward, CA). Cells were cultured per the manufacturer’s protocol in Ham’s F12K media (ThermoFisher, Waltham, MA), with 10% heat inactivated fetal bovine serum (Hyclone, Logan, UT) and 600 µg / mL Zeocin (Invivogen, San Diego, CA), and stored in frozen aliquots to be used as assay ready cells. On the day of the assay, cells were removed from frozen storage, washed two times in 1x Kreb’s Ringer Buffer (Zenbio, Research Triangle Park, NC), and re-suspended to a concentration of 4 x 105cells / mL in 1x Kreb’s Ringer Buffer with 0.1% bovine serum albumin (BSA, Sigma Aldrich, St. Louis, MO) and 0.125 mM 3-isobutyl-1-methylxanthine (IBMX, Sigma Aldrich, St. Louis, MO).50 nL of test compound in 100% DMSO spanning a final concentration range of 3 x 10-08– 5.08 x 10-13M were acoustically dispensed in low volume, white, 384-well polypropylene plates (Corning, Tewksbury, MA), followed by the addition of 4 x 103cells per well in total volume of 10 µL. Cells were incubated with test compound for 1 hour (hr) at room temperature in the dark, and cAMP accumulation was measured using the Cisbio HiRange cAMP assay kit (Bedford, MA) per the manufacturer’s protocol. Anti-cAMP antibody and d2-cAMP tracer reagents diluted in lysis / detection buffer were incubated in the dark for 1 hr, and results were measured on an Envision plate reader (Perkin Elmer, Waltham, MA). Data was normalized using 10 59057274.1nM GIP as 100% activity, and DMSO alone as 0% activity.

[0604] HEK-293T cells overexpressing full-length human GLP-1R with a sequence identical toGenBank accession number NM_002062 with an N-terminal FLAG tag may be purchased from Multispan, Inc (Hayward, CA). Cells were cultured per the manufacturer’s protocol in DMEM with 10% fetal bovine serum and 1 µg / mL puromycin and stored in frozen aliquots to be used as assay ready cells. On the day of the assay, cells were removed from frozen storage, washed two times in 1x Kreb’s Ringer Buffer (Zenbio, Research Triangle Park, NC) and re-suspended to a concentration of 4 x 105cells / mL in 1x Kreb’s Ringer Buffer with 0.1% bovine serum albumin (BSA, Sigma Aldrich, St. Louis, MO) and 0.25 mM 3-isobutyl-1-methylxanthine (IBMX, Sigma Aldrich, St. Louis, MO).50 nL of test compound in 100% DMSO spanning a final concentration range of 1 x 10-6– 1.69 x 10-11M were acoustically dispensed in low volume, white, 384-well polypropylene plates (Corning, Tewksbury, MA), followed by the addition of 4 x 103cells per well in total volume of 10 µL. Cells are incubated with test compound for 1 hr at room temperature in the dark, and cAMP accumulation was measured using the Cisbio HiRange cAMP assay kit (Bedford, MA) per the manufacturer’s protocol. Anti-cAMP antibody and d2-cAMP tracer reagents diluted in lysis / detection buffer were incubated in the dark for 1 hr, and results were measured on an Envision plate reader (Perkin Elmer, Waltham, MA). Data is normalized using 1 nM GLP-1 as 100% activity, and DMSO alone as 0% activity.

[0605] Table 3. GIP Receptor Selective Activation of Various GIP Receptor Agonist Peptidesof the Disclosure Compound Sequence ID Human GIPR cAMP, Human GLP1R cAMP No. No. pEC50pEC50A 2 9.3 8.2B 3 9.97 <6.00C 4 9.18 6.06D 5 9.06 <6.00E 6 9.16 7.57F 7 9.48 859057274.1G 8 9.43 <6.00H 9 9.38 <6.00I 10 9.35 <6.00J 11 9.13 6.81K 12 9.24 <6.00

[0606] Table 3 provides the selective functional activity of the GIPR agonist peptides of thepresent disclosure. As can be seen, the peptide compounds provided here have a human GLP1R cAMP pEC50 / human GIPR cAMP pEC50ratios ranging from about 1.2 to greater than 2, thus indicating incredibly selective GIPR agonist functional activity. Most of the GIPR agonist peptide compounds display Human GLP1R cAMP pEC50 / Human GIPR cAMP pEC50 ratios of greater than 1,000, or greater than 5,000, or greater than 10,000, or greater than 50,000, or greater than 100,000.

[0607] Example 6 - PYY-1119-Induced Emesis in Dogs

[0608] Female beagle dogs (20-43 months old) are fasted for approximately 16 hours andtransferred to an observation cage without food before each emetogen challenge. The dogs are weighed with an electronic balance, then test articles are administered via the subcutaneous route. The effects of single subcutaneous administration of the GIPR agonist compounds of the present disclosure on Neuropeptide Y2 receptor (Y2R) agonist compound PYY-1119 (PYY; 4- imidazolecarbonyl-Ser-D-Hyp-Iva-Pya(4)-Cha-Leu(Me)-Asn-Lys-Aib-Thr-Arg-Gln-Arg-Cha-NH2;10 μg / kg [about 5 nmol / kg]; s.c.) induced emesis are evaluated in dogs. The GIPR agonist peptidecompounds of the present disclosure and vehicles (1: 0.09% [w / v] Tween 80 / 10% DMSO / PBS; 2: 59057274.10.01mol / L PBS) are administered subcutaneously (sc) at different doses to dogs, followed by sc injections with PYY-1119 at 8 & 72 hours post-dose. Emesis symptoms are continuously recorded using a video camera and observations of symptoms include retching (a rhythmic contraction of the abdomen) and vomiting (vomiting behavior, including the elimination of vomitus or similar behavior). The combination of retching and vomiting is defined as emesis, and the number of episodes, latency (time elapsed from PYY administration until the onset of the first emesis symptom), duration (time elapsed between the onset of the first and final episodes of emesis), and frequency (number of animals showing emesis / number of experimental animals) of each of these symptoms was calculated. The latency in cases where emesis symptoms are not noted is taken as the maximum value (8 hours for PYY challenge) at the end of observation. When the duration of the emesis symptoms is less than 1 min, the duration is recorded, for convenience, as 1 min.

[0609] Emetic episodes (sum of retching and vomiting) are counted for 2 hours afteradministration (by blinded analysis).

[0610] The indicated compounds are each administered at 30 nmol / kg, all s.c.(subcutaneously), and the number of emetic events are indicated. In Table 4, each value represents the mean ± S.D. (n=4). The latency of a dog that did not show emetic response is considered as 120 min. The duration shown is the cumulative total duration of vomiting response. 59057274.1The vehicle is provided at 0.01 mol / L PBS 0.5 mL / kg, s.c. The compounds disclosed herein inhibit PYY-1119-induced emesis, including symptoms of vomiting.

[0611] Example 7: Morphine-Induced Emesis in Ferrets

[0612] 1. Effect of subcutaneously administered GIP receptor agonist peptide in morphine-induced acute emetic model.

[0613] The ferrets are weighed using an electronic balance and transferred to an observation cagewithout food and water approximately 30 minutes (min) after feeding. Approximately 30 min later, morphine was administered. Thereafter, for 1 hour post-administration, their emesis symptoms are macroscopically observed. At the same time, these symptoms are continuously recorded using a video camera. Observation symptoms included retching (rhythmic contraction of the abdomen), vomiting (vomiting behavior, including elimination of vomitus or similar behavior), licking (licking chops), and fidgeting (fidgety movements). The number of episodes and occurrences of these symptoms are recorded. In addition, the combination of retching and vomiting is defined as emesis, and the number of episodes, latency (time elapsed from morphine administration until the onset of the first emesis symptom), duration (time elapsed between the onset of the first and final episodes of emesis), and frequency (number of animals showing emesis / number of experimental animals) of each of these symptoms are calculated. The latency in cases where emesis symptoms are not noted 59057274.1is taken as the maximum value (30 min) at the end of observation. When the duration of the emesis symptoms is less than 1 min, the duration is recorded, for convenience, as 1 min.

[0614] GIP receptor agonist peptides are dissolved with a vehicle (0.09 w / v% tween 80 / 10%DMSO / saline), respectively, to prepare test solutions.0.5 mg / kg of the test solutions and the vehicle were subcutaneously administered to ferrets (4 in each group), respectively. At a time of 0.5 to 2 hours after administration, 0.6 mg / kg of morphine is subcutaneously administered. Up to 60 minutes after morphine administration, the condition of the ferrets was monitored to record the number of animals that did not vomit, the number of emetic episodes, the latency period in minutes to observe the emetic episodes, the duration of the observed emesis if any.

[0615] Example 8: Apomorphine Induced Emesis in Dogs

[0616] This Example shows the results of the administration of exemplary GIPR agonistcompounds (10, 30 and 100 nmol / kg, s.c., respectively) on apomorphine (0.1 mg / kg, s.c.)-induced emesis in dogs. The vehicle is provided at 0.01 mol / L PBS 0.5 mL / kg, s.c. In this study, dogs (8- 12 months old; n = 4) were transferred to an observation cage without food on 1 day before each emetogen challenge. The dogs are weighed by using an electronic balance then test articles will be administrated via the subcutaneous route. The GIPR agonist peptide compounds of the present disclosure and vehicle (0.01mol / L PBS) is administered subcutaneously (sc) at different doses to 59057274.1female beagle dogs followed by sc injections with apomorphine is challenged at 8 & 72 hours in the table post-dose. Emetic events were monitored for 1 h by video recording. Emesis symptoms are continuously recorded using a video camera and observations of symptoms included retching (a rhythmic contraction of the abdomen) and vomiting (vomiting behavior, including the elimination of vomitus or similar behavior). Besides, the combination of retching and vomiting is defined as emesis, and the number of episodes, latency (time elapsed from morphine administration until the onset of the first emesis symptom), duration (time elapsed between the onset of the first and final episodes of emesis), and frequency (number of animals showing emesis / number of experimental animals) of each of these symptoms is calculated. The latency in cases where emesis symptoms are not noted is taken as the maximum value (8 hours for apomorphine challenge) at the end of observation. When the duration of the emesis symptoms is less than 1 min, the duration is recorded, for convenience, as 1 min.

[0617] The compounds suppressed the apomorphine-induced emetic symptoms. In this tablebelow, results are shown as percent inhibition (%) at the dose of compound (nmol / kg) shown, at the hour(s) postdose of apomorphine, calculated as (1- (number of emetic episodes with peptide compound / number of emetic episodes with vehicle)) X 100.

[0618] The compounds are effective in inhibiting the frequency of emetic events in dogs dosed59057274.1with apomorphine.

[0619] Example 9: Human and Dog Plasma Protein Binding (PPB)

[0620] Stock Solutions

[0621] Stock solutions: (2000 µM) of the peptides are prepared in DMSO.

[0622] Plasma Protein Binding (PPB) Analysis

[0623] Human plasma (male; containing K2-EDTA as anti-coagulant; pre-adjusted to pH 7.4 -NB alternative species may be used) is spiked individually with each test peptide (2000 nmol / L), sampled for analysis and then incubated (n=4) at 37°C in a water bath for 30 minutes. Following the incubation period, the plasma is sampled for analysis, then transferred to ultracentifugation tubes and centrifuged (n=3) at -155,000g and 4°C for 4 hours, after which the supernatant is sampled for analysis. An additional aliquot of the supernatant is taken at the end of the centrifugation period to determine the total protein concentration. An aliquot of the incubated plasma will be stored at 4°C for 4 hours and then sampled for analysis. At the point of sampling, all samples are matrix-matched, treated with 4% phosphoric acid in water (1:1 (vfv)) containing internal standard, centrifuged at 2000g and 4°C for 10 minutes and stored prior to LC-MS / MS analysis. An appropriate positive control compound control will be incubated and centrifuged in parallel. Fraction unbound (Fu) values is determined by comparison of the analyte response in plasma to the analyte response in the 59057274.1supernatant, determined via peak area response ratios.

[0624] Sample Analysis

[0625] The samples are analyzed by LC-MS / MS using a 6500 (or equivalent) triple quadrupolemass spectrometer (AB Sciex) coupled to an appropriate Liquid Chromatography (LC) system. Protein binding and stability values are determined via peak area ratios using multiple reaction monitoring (MRM) parameters following compound optimization. Multiple reaction monitoring (MRM) is a highly sensitive method of targeted mass spectrometry (MS) that can be used to selectively detect and quantify peptides based on the screening of specified precursor peptide-to- fragment ion transitions.

[0626] Dog PPB values presented below are obtained essentially as described for Human PPBsamples, with the difference being that dog plasma was used instead of human serum. Table 8 is provided with the values of (Fu, plasma) as fraction unbound expressed as a percentage compared to the percent bound i.e. if the value is 0.0123, then the fraction unbound is (0.0123 / 100)%, which is 1.23% of the peptide is unbound and 98.77% is bound in plasma.

[0627] The GIPR agonist peptides of the present disclosure provide a percent of unbound oractive drug for antiemetic activity, which ranges from about 0.1% to about 10%. The efficacy of the GIPR agonist peptide will be related to the exposure to the amount of unbound drug in plasma, 59057274.1i.e. the proportion of free peptide to penetrate into surrounding tissues. The bound peptide in plasma can also serve as a reservoir for free peptide removed by various elimination processes thus prolonging the duration of action. GIPR agonist peptides of the present disclosure provide an optimum range of peptide unbound to plasma protein for once daily dosing to human subjects between 1-10% unbound. It is believed that GIPR agonist peptides of the present disclosure having a free fraction of about 1% to about 10% translates to a peptide having a desirable PK profile, demonstrating fast absorption and fast elimination to prevent excessive accumulation.

[0628] Example 10: Solubility of the GIPR Agonist Compounds

[0629] 3 mg of peptides are weighted out in a small glass vial. 100uL of 200mM Phosphatebuffer pH 7.4 are added and the vial is sonicated / vortexed as necessary for a maximum of 1 min. A visual inspection is performed, If the sample is fully dissolved, the solubility is recorded as 30mg / mL. If insoluble material is observed in the tube the addition of 100uL of buffer and mixing is repeated until complete dissolution. If the peptide is not soluble in 500uL of buffer, it is labeled as solubility < 6mg / mL. The solubility can be confirmed by RP-HPLC after filtration on 0.2μm filter on an Agilent 1200 system with a Kinetex column form Phenomenex® (2.6µm EVO C18 100 Å, LC Column 50 x 3.0 mm) kept at 40⁰C, the eluent A is 0.05% TFA in Water, B is 0.035% TFA in Acetonitrile at a 0.6ml / min flow rate. The gradient was from 20 to 70 over 5 min, the column is then 59057274.1washed for 1min at 90% B. UV monitoring at 215nm was used to monitor peptide concentration.

[0630] Table 7. Results of the Solubility of the Compounds in Phosphate Buffer at pH 7.4:Compound SEQ ID pH 7.4 Phosphate No. No. Buffer - Solubility (mg / mL) A2 30B 3 30C 4 30D 5 15E 6 15F 7 30G 8 15H 9 30I 10 15J 11 15K 12 15

[0631] As shown in Table 7, several of the tested GIPR agonist peptides demonstrate highsolubility in physiological buffer (Phosphate buffer at pH 7.4) of 15 mg / mL and above. Several compounds, including Compounds A, B, C, D, E, and F exhibit a solubility in phosphate buffer at pH 7.4 of 20 mg / mL or greater, which are the preferred compounds for dosing in volumes that facilitate QW dosing. Compounds having a solubility of less than 20 mg / mL, for example less than 20 mg / mL, or from 10mg / mL to 20 mg / mL are less preferred, and peptide compounds having less than 10mg / mL solubility as described in Example 10 are excluded from the GIPR agonist peptides that are suitable for QW dosing. In some embodiments, GIPR agonist peptide compounds of the present disclosure having less than 15mg / mL solubility are excluded from the GIPR agonist peptides that are suitable for QW dosing. 59057274.1

[0632] Example 11: Summary of Pharmacokinetic (PK) and Pharmacodynamic (PD)Studies of Selective GIP Receptor Agonist Peptides.

[0633] Pharmacokinetic (PK) studies are conducted in dogs in order to determine the half-lifeafter IV and SC dosing. Each of the peptide compounds is dissolved in PBS pH 7.4 to a concentration of 3nmol / mL and the animals are dosed with a volume of 1mL / kg SC or IV. Blood samples are collected at 0, 0.0330, 0.0830, 0.250, 0.500, 1.00, 2.00, 4.00, 6.00, 8.00, 12.0, 24.0, 48.0 hours for IV dosing and 0.250, 0.500, 1.00, 2.00, 4.00, 6.00, 8.00, 12.0, 24.0, 48.0 for SC dosing, EDTA-K2 was used as anticoagulant. The plasma concentration of each of the peptides is measured using LCMS. Allometric scaling of lipidated peptide pharmacokinetics including T1 / 2 and MRT is known in the art for rodent to dog and mini pig and to humans. In one illustrative embodiment, a lipidated peptide is shown to have MRT = 16.5 hrs following s.c. dosing in dog and is dosed QD in humans. See for example, Discovery and Development of Liraglutide and Semaglutide. Knudsen, L. B.; Lau, J. Frontiers in Endocrinology, 2019, vol 10, Article 155.

[0634] Certain peptide compounds demonstrate exemplary pharmacokinetic activity providingthe optimal exposure for once per day dosing. The IV half life (data provided for dogs) can beextrapolated to human exposure ranging from IV half lives ranging from 6 to 16 hours when dosedat 3 nmol / kg.

[0635] Example 12. Pharmacological Profile of Exemplary GIPr Agonist Peptides59057274.1

[0636] Disclosed below and herein are GIPr agonist peptides with an alternative pharmacologicalprofile, including in vitro data on receptor binding, functionalization, signaling, and / or recruitment. The following in vitro assays were conducted: dog GIPR cAMP production, human GIPR binding, human GIPr and dog Ca2+flux, and human and dog GIPr arrestin recruitment. The assays were conducted as disclosed in the Examples herein.

[0637] Human GIPR Calcium Flux Assay

[0638] HEK-293T cells stably overexpressing high levels of full-length human GIPR with asequence identical to GenBank accession number NM_000164 with an N-terminal FLAG tag were purchased from Multispan, Inc (Hayward, CA). Cells were cultured per the manufacturer’s protocol in DMEM (ThermoFisher, Waltham, MA) with 10% heat inactivated fetal bovine serum (Hyclone, Logan, UT) and 1 µg / mL puromycin (ThermoFisher, Waltham, MA). The day before the assay, 5 µL of Matrigel (Corning, Tewksbury, MA) was added to a black, 384-well plate with clear bottom (Corning, Tewksbury, MA), centrifuged for 2 min at 1,000g, and incubated at 37⁰C for 10 min. GIPR- 293T cells were detached from the cell culture flask, and 20,000 cells in cell culture media were added to each well. Cells were incubated overnight (~16 hours), and the following day, Calcium 6 dye (Molecular Devices, San Jose, CA) was prepared according to the manufacturer’s protocol. Cell culture media was aspirated from each well and replaced with 50 µL of loading dye with 0.1% BSA, 59057274.1incubated for 2 hours at 37⁰C, and calcium flux in response to agonist peptide spanning a final concentration range of 5 x 10-6– 8.47 x 10-11M was measured using the FLIPR Tetra system equipped with EMCCD camera (Molecular Devices, San Jose, CA). Data was normalized using 5 µM GIP as 100% activity, and DMSO alone as 0% activity.

[0639] Human GIPR HiBiT Internalization Assay

[0640] The ability of agonist peptides to cause internalization of the GIPR was measuredusing HiBiT technology (Promega, Madison, WI). CHO-K1 cells stably expressing full-length GIPR with a HiBiT tag (Promega, Madison, WI) fused to the N-terminus and connected to the GIPR by linker sequence GNSGSSGGGGSGGGGSGG was created using standard molecular biology approaches. Cells were cultured in F12K containing 600 µg / mL geneticin and 10 µg / mL blasticidin (ThermoFisher, Waltham, MA), along with 10% heat inactivated fetal bovine serum (Hyclone, Logan, UT).100,000 cells / well were added to a white, 96-well tissue culture treated plate (Corning, Tewksbury, MA) and incubated at 37⁰C overnight (~16 hours). On the day of the assay, culture media was replaced with F12K containing 0.1% BSA (Sigma Aldrich, St. Louis, MO), and incubated for 30 min at 37⁰C. Media is then removed and replaced with similar media now containing 0.01% cycloheximide (Sigma Aldrich, St. Louis, MO). Agonist peptides were added spanning a concentration range of 1 x 10-6– 1.69 x 10-11M, and incubated for 3 hr at 37⁰C. At the end of the 59057274.1incubation period, plates are allowed to equilibrate to room temperature for 10 min. Nano-Glo HiBiT Extracellular Detection Reagent (Promega, Madison, WI) is prepared according to the manufacturer’s protocol, and added to the assay plate. Cells are further incubated for 10 min, and luminescence is read on an Envision plate reader (Perking Elmer, Waltham, MA). Data was normalized using 1 µM GIP as 100% activity / receptor internalization, and DMSO alone as 0% activity / receptor internalization.

[0641] Canine (Dog) GIPR cAMP Assay

[0642] HEK-293T cells stably overexpressing full-length canine GIPR with a sequenceidentical to GenBank accession number XM_014119637 with an N-terminal FLAG tag were purchased from Multispan, Inc (Hayward, CA). Cells were cultured per the manufacturer’s protocol in DMEM media (ThermoFisher, Waltham, MA), with 10% heat inactivated fetal bovine serum (Hyclone, Logan, UT) and 1 µg / mL puromycin (ThermoFisher, Waltham, MA), and stored in frozen aliquots to be used as assay ready cells. On the day of the assay, cells were removed from frozen storage, washed two times in 1x Kreb’s Ringer Buffer (Zenbio, Research Triangle Park, NC), and re- suspended to a concentration of 4 x 105cells / mL in 1x Kreb’s Ringer Buffer with 0.1% bovine serum albumin (BSA, Sigma Aldrich, St. Louis, MO) and 0.25 mM 3-isobutyl-1-methylxanthine (IBMX, Sigma Aldrich, St. Louis, MO). 50 nL of test compound in 100% DMSO spanning a final 59057274.1concentration range of 3 x 10-08– 5.08 x 10-13M were acoustically dispensed in low volume, white, 384-well polypropylene plates (Corning, Tewksbury, MA), followed by the addition of 4 x 103cells per well in total volume of 10 µL. Cells were incubated with test compound for 1 hr at room temperature in the dark, and cAMP accumulation was measured using the Cisbio HiRange cAMP assay kit (Bedford, MA) per the manufacturer’s protocol. Anti-cAMP antibody and d2-cAMP tracer reagents diluted in lysis / detection buffer were incubated in the dark for 1 hr, and results were measured on an Envision plate reader (Perkin Elmer, Waltham, MA). Data was normalized using 10 nM GIP as 100% activity, and DMSO alone as 0% activity. Results can be found in Table 11.

[0643] Canine Arrestin Assay

[0644] The ability of canine GIPR to recruit canine β-arrestin2 in the presence of agonist wasmeasured using NanoBRET technology (Promega, Madison, WI). Briefly, CHO-K1 cells were engineered to stably express canine GIPR with a C-terminal LgBiT fusion and β-arrestin2 with a N- terminal SmBiT fusion. The sequence for canine GIPR was identical to Uniprot ID E2RIK5, while β-arrestin2 sequence corresponded to E2QUH6. Clonal cells were cultured in Ham’s F12K (ThermoFisher, Waltham, MA), with 10% heat inactivated FBS (Hyclone, Logan, UT), 800 µg / mL Zeocin (Invivogen, San Diego, CA), and 600 µg / mL Geneticin (ThermoFisher, Waltham, MA), and stored in frozen aliquots to be used as assay ready cells. On the day of the assay, cells were removed 59057274.1from frozen storage, washed two times in CO2 independent media (Invitrogen, Waltham, MA) supplemented with GlutaMax (Invitrogen, Waltham, MA) and 0.1% bovine serum albumin (Sigma Aldrich, St. Louis, MO). Cells were resuspended in similar wash buffer supplemented with 1x NanoGlo Live substrate (Promega, Madison, WI) to 6 x 105cells / mL. 50 nL of test compound in 100% DMSO spanning a final concentration range of 1 x 10-6– 1.69 x 10-11M were acoustically dispensed in low volume, white, 384-well polypropylene plates (Corning, Tewksbury, MA), followed by the addition of 6 x 103cells per well in total volume of 10 µL. Cells were incubated with test compound for 30 min at room temperature in the dark, and arrestin recruitment was measured using a luminescent readout on an Envision plate reader (Perkin Elmer, Waltham, MA). Data was normalized using 1 µM GIP as 100% activity, and DMSO alone as 0% activity.

[0645] Canine GIPR Calcium Flux Assays

[0646] HEK-293T cells stably overexpressing high levels of canine GIPR with a sequenceidentical to Uniprot ID E2RIK5 with an N-terminal FLAG tag were purchased from Multispan, Inc (Hayward, CA). Cells were cultured per the manufacturer’s protocol in DMEM (ThermoFisher, Waltham, MA) with 10% heat inactivated fetal bovine serum (Hyclone, Logan, UT) and 1 µg / mL puromycin (ThermoFisher, Waltham, MA). The day before the assay, 5 µL of Matrigel (Corning, Tewksbury, MA) was added to a black, 384-well plate with clear bottom (Corning, Tewksbury, MA), centrifuged for 2 min at 1,000g, and incubated at 37⁰C for 10 min. Canine GIPR-293T cells were 59057274.1detached from the cell culture flask, and 20,000 cells in cell culture media were added to each well. Cells were incubated overnight (~16 hours), and the following day, Calcium 6 dye (Molecular Devices, San Jose, CA) was prepared according to the manufacturer’s protocol. Cell culture media was aspirated from each well and replaced with 20 µL of loading dye with 0.1% bovine serum albumin, incubated for 2 hours at 37⁰C, and immediate calcium flux in response to agonist peptide spanning a final concentration range of 5 x 10-6– 8.47 x 10-11M was measured using the FLIPR Tetra system equipped with EMCCD camera (Molecular Devices, San Jose, CA). Data was normalized using 5 µM GIP as 100% activity, and DMSO alone as 0% activity. Table 8. In Vitro Ca2+ Assays for Exemplary Compounds SEQ ID D manHuman og No.HuDog GIPR GIPR GIPR Compound No. GIPR Ca2+ Ca2+ Ca2 Ca2+ pEC50 + Emax (%) pEC50 Emax (%) A 2 <5.30 1.3 <5.30 2.8 B3<5.30 2.7 <5.30 9.3 C4<5.30 3 <5.30 0 D 5 <5.30 5.4 <5.30 2.5 E 6 <5.30 1.5 <5.30 52.5 F7<5.30 1.1 <5.30 54.1 G8<5.30 2.67 <5.30 5.44 H 9 <5.30 3.36 <5.30 7.85 I 10 <5.30 2.43 <5.30 4.72 J11<5.30 2 <5.30 4.98 K12<5.30 0.89 <5.30 2.86 59057274.1Table 9. In Vitro Arrestin Assays for Exemplary Compounds SEQ ID NoHumanHuman o. G Dog GIPR Dog GIPR Compound N IPR GIPR Arrestin Arrestin Arrestin Arrestin pEC50 Emax (%) pEC50 Emax (%) A28.26 39.2 7.66 8.6 B 3 8.22 25.5 8.24 7.9 C48.39 42.5 7.49 8.1 D58.31 38.2 7.86 6.2 E68.27 39.3 8.06 6.3 F 7 8.58 38.7 8.47 7.4 G88.93 10.46 <6.00 1.05 H98.38 21.76 7.86 2.52 I108.71 10.9 <6.00 0.93 J 11 8.15 17.98 7.2 3.31 K128.86 10.91 <6.00 0.7 Table 10. In Vitro Dog GIPR cAMP Assays for Exemplary Compounds SEQ ID No Compound No. Dog GIPR cAMP pEC50 A29.36 B39.65 C49.34 D59.32 E69.67 F79.89 G89.27 H99.11 I109.15 J118.98 K129.09 59057274.1

[0647] Example 13. β-Arrestin Signaling Assays

[0648] The ability of human GIPR to recruit β-arrestin2 in the presence of agonist is measuredusing NanoBRET technology (Promega, Madison, WI). Briefly, CHO-K1 cells are engineered to stably express human GIPR with a C-terminal LgBiT fusion and β-arrestin2 with a N-terminal SmBiT fusion. Clonal cells are cultured in Ham’s F12K (ThermoFisher, Waltham, MA), with 10% heat inactivated FBS (Hyclone, Logan, UT), 800 µg / mL Zeocin (Invivogen, San Diego, CA), and 600 µg / mL Geneticin (ThermoFisher, Waltham, MA), and stored in frozen aliquots to be used as assay ready cells. On the day of the assay, cells are removed from frozen storage, washed two times in CO2 independent media (Invitrogen, Waltham, MA) supplemented with GlutaMax (Invitrogen, Waltham, MA) and 0.1% BSA (Sigma Aldrich, St. Louis, MO). Cells are resuspended in similar wash buffer supplemented with 1x NanoGlo Live substrate (Promega, Madison, WI) to 6 x 105cells / mL.50 nL of test compound in 100% DMSO spanning a final concentration range of 1 x 10-6– 1.69 x 10-11M are acoustically dispensed in low volume, white, 384-well polypropylene plates (Corning, Tewksbury, MA), followed by the addition of 6 x 103cells per well in total volume of 10 µL. Cells are incubated with test compound for 30 min at room temperature in the dark, and arrestin recruitment is measured through luminescent readout on an Envision plate reader (Perkin Elmer, Waltham, MA). Data is normalized using 1 µM GIP as 100% activity, and DMSO alone as 0% activity. 59057274.1

[0649] Table 11. Human GIPR β-Arrestin Emax Values When Treated With GIP ReceptorAgonist Peptides of the Present Disclosure. Compound No. SEQ ID NO: GIPR β-Arrestin EmaxA 2 39.2B 3 25.5C 4 42.5D 5 38.2E 6 39.3F 7 38.7G 8 10.5H 9 21.8I 10 10.9J 11 18.0K 12 10.9

[0650] In some embodiments, GIPR agonist peptide compounds of the present disclosure havinga human β-Arrestin Emaxgreater than 30% as described in Example 13 are excluded from the GIPR agonist peptides that are suitable for Q1D dosing. Formulation Example 1 (1) Compound A 10.0 mg (2) Lactose 70.0 mg (3) Cornstarch 50.0 mg (4) Soluble starch 7.0 mg (5) Magnesium stearate 3.0 mg

[0651] Compound A (10.0 mg) and magnesium stearate (3.0 mg) are granulated with an aqueoussoluble starch solution (0.07 mL) (7.0 mg as soluble starch), dried and mixed with lactose (70.0 mg) 59057274.1and cornstarch (50.0 mg). The mixture is compressed to give a tablet. Formulation Example 2 (1) Compound A 5.0 mg (2) Sodium chloride 20.0 mg (3) Distilled water to total amount 2 mL

[0652] Compound A (5.0 mg) and sodium chloride (20.0 mg) are dissolved in distilled water,and water is added to a total amount of 2.0 ml. The solution is filtered, and filled in a 2 ml ampoule under aseptic conditions. The ampoule is sterilized and tightly sealed to give a solution for injection. Industrial Applicability

[0653] The GIP receptor agonist peptides of the present disclosure have superior GIP receptorselective agonist activity, and are useful as a drug for the prophylaxis or treatment of emesis and conditions caused by associated with GIP receptor activity, for example, emesis and diseases associated with vomiting or nausea and the like. In one embodiment, the selective GIP receptor agonist peptides are useful as a drug or medicament, or for use in the prophylaxis or treatment of emesis and conditions caused by associated with GIP receptor activity, for example cyclic vomiting 59057274.1syndrome, and nausea and / or vomiting associated with administration of a chemotherapeutic or anti- cancer agent as illustrated herein.

[0654] All the publications, patents, and the patent applications cited herein are incorporatedherein by reference in their entireties. SEQ ID NO: 1: Natural human GIP SEQ ID NO: 2 to 12: Synthetic GIPR agonist peptides (e.g., examples of Formulae (I), (I-A), and / or (I-B) OTHER EMBODIMENTS

[0655] It is to be understood that while claimed subject matter has been described in conjunctionwith the detailed description thereof, the foregoing description is intended to illustrate and not limit the scope of the claimed subject matter. Other aspects, advantages, and modifications are within the scope of the claims. 59057274.1

Claims

CLAIMS1. A GIP receptor agonist peptide represented by Formula (I):P1-Tyr-Aib-Glu-Gly-Thr-A6-A7-Ser-A9-Tyr-A11-Ile-A13-A14-A15-A16-A17-A18-Gln- A20-A21-Phe-Val-A24-A25-A26-A27-A28-A29-A30-A31-A32-A33-A34-A35-A36-A37-A38- A39-A40-P2(SEQ ID NO: 13), or a pharmaceutically acceptable salt thereof; wherein P1is: H or methyl; P2is: -NH2 or -OH; A6 is: Ala, Leu, Phe, Thr, or Val; A7 is: Ile or Val; A9 is any amino acid other than Glu or Asp; A11 is: Ser or Phe; A13 is: Aib or Ala; A14 is: Leu, Nle, Met, or Lys(R); A15 is: Asp or Glu; A16 is: Arg or Lys; A17 is: Leu, Glu, Gln, Aib, Ile, or Lys(R); 59057274.1A18 is: Ala, His, or Lys(R); A20 is: Aib, Lys, or Lys(R); A21 is: Glu, Asn, Asp, Lys, Gln, or Lys(R); A24 is: Glu, Asn, Gln, Lys, or Lys(R); A25 is: Ser, Tyr, Trp, or Lys(R); A26 is: Leu or Iva; A27 is: Leu or Ala; A28 is: Ala or Lys; A29 is: Gly, Gln, or Lys(R); A30 is: Glu, Gly, Arg, Lys, or Lys(R); A31 is: Pro or Gly; A32 is: Ser or a deletion; A33 is: Ser or a deletion; A34 is: Gly or a deletion; A35 is: Ala or a deletion; A36 is: Pro or a deletion; A37 is: Pro or a deletion; 59057274.1A38 is: Pro or a deletion; A39 is: Ser or a deletion; A40 is: Lys, Arg, or a deletion; wherein at least one of A14, A17, A18, A20, A21, A24, A25, A29, or A30 is Lys(R); and wherein in the residue Lys(R), the (R) portion represents -L-X, wherein L represents a linker and is selected from the group consisting of 1OEGgE, 2OEG, 2OEGgE, 2OEGgEgE, 2OEGgEgEgE, 3OEGgE, 3OEGgEgE, G3gEgE, G4gE, G4gEgE, GGGGG, G5gE, G5gEgE, OEGgEgE, and OEGgEgEgE; and X represents C17-C22 monoacid or C17-C22 diacid.

2. The GIP receptor agonist peptide of claim 1, or the pharmaceutically acceptable salt thereof,wherein the GIP receptor agonist peptide is of Formula (I-A): P1-Tyr-Aib-Glu-Gly-Thr-Val-A7-Ser-Leu-Tyr-A11-Ile-A13-A14-Asp-A16-A17-A18-Gln- A20-A21-Phe-Val-A24-Trp-A26-A27-A28-A29-A30-A31-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser-A40- P2(SEQ ID NO: 14), or a pharmaceutically acceptable salt thereof; wherein P1is: H or methyl; P2is: -NH2or -OH; 59057274.1A7 is: Ile or Val; A11 is: Ser or Phe; A13 is: Aib or Ala; A14 is: Leu, Nle, Met, or Lys(R); A16 is: Arg or Lys; A17 is: Leu, Glu, Gln, Aib, Ile, or Lys(R); A18 is: Ala, His, or Lys(R); A20 is: Aib, Lys, or Lys(R); A21 is: Glu, Asn, Asp, Lys, Gln, or Lys(R); A24 is: Glu, Asn, Gln, Lys, or Lys(R); A26 is: Leu or Iva; A27 is: Leu or Ala; A28 is: Ala or Lys; A29 is: Gly, Gln, or Lys(R); A30 is: Gly, Arg, Lys, or Lys(R); A31 is: Pro or Gly; A40 is: Lys, Arg, or a deletion; 59057274.1wherein at least one of A14, A17, A18, A20, A21, A24, A25, A29, or A30 is Lys(R); and wherein in the residue Lys(R), the (R) portion represents -L-X, wherein L represents a linker and is selected from the group consisting of 1OEGgE, 2OEG, 2OEGgE, 2OEGgEgE, 2OEGgEgEgE, 3OEGgE, 3OEGgEgE, G3gEgE, G4gE, G4gEgE, GGGGG, G5gE, G5gEgE, OEGgEgE, and OEGgEgEgE; and X represents C17-C22 monoacid or C17- C22 diacid.

3. The GIP receptor agonist peptide of claim 1, or the pharmaceutically acceptable salt thereof,wherein A6 is Val.

4. The GIP receptor agonist peptide of claim 1 or 3, or the pharmaceutically acceptable saltthereof, wherein A9 is Ala, Arg, Asn, Cys, Gln, Gly, His, Ile, Leu, Lys, Met, Phe, Pro, Ser, Thr, Trp, Tyr, or Val.

5. The GIP receptor agonist peptide of any one of claims 1, 3, or 4, or the pharmaceuticallyacceptable salt thereof, wherein A9 as Leu. 59057274.

16. The GIP receptor agonist peptide of any one of claims 1 or 3-5, or the pharmaceuticallyacceptable salt thereof, wherein A15 is Asp.

7. The GIP receptor agonist peptide of any one of claims 1 or 3-6, or the pharmaceuticallyacceptable salt thereof, wherein A25 is Trp.

8. The GIP receptor agonist peptide of any one of claims 1 or 3-7, or the pharmaceuticallyacceptable salt thereof, wherein A30 is Gly, Arg, Lys, or Lys(R).

9. The GIP receptor agonist peptide of any one of claims 1 or 3-9, or the pharmaceuticallyacceptable salt thereof, wherein A32-A39 is Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser.

10. The GIP receptor agonist peptide of any one of claims 1 or 3-9, or the pharmaceuticallyacceptable salt thereof, wherein A7 is Val.

11. The GIP receptor agonist peptide of claim 1 or 2, or the pharmaceutically acceptable saltthereof, wherein the GIP receptor agonist peptide is: 59057274.1P1-Tyr-Aib-Glu-Gly-Thr-Val-Val-Ser-Leu-Tyr-A11-Ile-A13-A14-Asp-A16-A17- A18-Gln-A20-A21-Phe-Val-A24-Trp-A26-A27-A28-A29-A30-A31-Ser-Ser-Gly-Ala- Pro-Pro-Pro-Ser-A40-P2, or a pharmaceutically acceptable salt thereof.

12. The GIP receptor agonist peptide of any one of claims 1-11, or the pharmaceuticallyacceptable salt thereof, wherein A11 is Ser.

13. The GIP receptor agonist peptide of any one of claims 1-12, or the pharmaceuticallyacceptable salt thereof, wherein A13 is Aib.

14. The GIP receptor agonist peptide of any one of claims 1-13, or the pharmaceuticallyacceptable salt thereof, wherein A14 is Leu or Lys(R).

15. The GIP receptor agonist peptide of any one of claims 1-14, or the pharmaceuticallyacceptable salt thereof, wherein A14 is Leu.

16. The GIPR agonist peptide of any one of claims 1-14, wherein A14 is Lys(R).59057274.

117. The GIP receptor agonist peptide of any one of claims 1-16, or the pharmaceuticallyacceptable salt thereof, wherein A16 is Arg.

18. The GIP receptor agonist peptide of any one of claims 1-17, or the pharmaceuticallyacceptable salt thereof, wherein A17 is Glu, Aib, Gln, or Lys(R).

19. The GIP receptor agonist peptide of any one of claims 1-18, or the pharmaceuticallyacceptable salt thereof, wherein A17 is Glu or Aib.

20. The GIP receptor agonist peptide of any one of claims 1-19, or the pharmaceuticallyacceptable salt thereof, wherein A17 is Glu.

21. The GIP receptor agonist peptide of any one of claims 1-18, wherein A17 is Lys(R).

22. The GIP receptor agonist peptide of any one of claims 1-21, or the pharmaceuticallyacceptable salt thereof, wherein A18 is Ala. 59057274.

123. The GIP receptor agonist peptide of any one of claims 1-22, or the pharmaceuticallyacceptable salt thereof, wherein A20 is Aib.

24. The GIP receptor agonist peptide of any one of claims 1-23, or the pharmaceuticallyacceptable salt thereof, wherein A21 is Glu, Asn, Lys, Gln, or Lys(R).

25. The GIP receptor agonist peptide of any one of claims 1-24, wherein A21 is Lys(R).

26. The GIP receptor agonist peptide of any one of claims 1-25, or the pharmaceuticallyacceptable salt thereof, wherein A24 is Glu, Asn, or Gln.

27. The GIP receptor agonist peptide of any one of claims 1-26, or the pharmaceuticallyacceptable salt thereof, wherein A24 is Asn.

28. The GIPR agonist peptide of any one of claims 1-25, wherein A24 is Lys(R).59057274.

129. The GIPR agonist peptide of any one of claims 1-28, wherein at least one of A14, A17, A21,A24, or A30 is Lys(R).

30. The GIPR agonist peptide of any one of claims 1-29, wherein in the residue Lys(R), the (R)portion represents -L-X, and L is selected from the group consisting of 2OEGgE, 2OEGgEgE, and GGGGG.

31. The GIPR agonist peptide of any one of claims 1-30, wherein L is 2OEGgE.

32. The GIPR agonist peptide of any one of claims 1-30, wherein L is 2OEGgEgE.

33. The GIPR agonist peptide of any one of claims 1-30, wherein L is GGGGG.

34. The GIPR agonist peptide of any one of claims 1-33, wherein X represents C17-C20 monoacid.

35. The GIPR agonist peptide of any one of claims 1-33, wherein X represents C17-C20 diacid.59057274.

136. The GIP receptor agonist peptide of any one of claims 1-35, or the pharmaceuticallyacceptable salt thereof, wherein A26 is Leu.

37. The GIP receptor agonist peptide of any one of claims 1-36, or the pharmaceuticallyacceptable salt thereof, wherein A28 is Ala.

38. The GIP receptor agonist peptide of any one of claims 1-37, or the pharmaceuticallyacceptable salt thereof, wherein A29 is Gly or Gln.

39. The GIP receptor agonist peptide of any one of claims 1-38, or the pharmaceuticallyacceptable salt thereof, wherein A29 is Gln.

40. The GIP receptor agonist peptide of any one of claims 1-39, or the pharmaceuticallyacceptable salt thereof, wherein A30 is Gly, Arg, or Lys(R).

41. The GIP receptor agonist peptide of any one of claims 1-40, or the pharmaceuticallyacceptable salt thereof, wherein A30 is Gly or Arg. 59057274.

142. The GIP receptor agonist peptide of any one of claims 1-41, or the pharmaceuticallyacceptable salt thereof, wherein A30 is Gly.

43. The GIP receptor agonist peptide of any one of claims 1-41, or the pharmaceuticallyacceptable salt thereof, wherein A30 is Arg.

44. The GIP receptor agonist peptide of any one of claims 1-43, or the pharmaceuticallyacceptable salt thereof, wherein A30-A31 is Arg-Pro.

45. The GIP receptor agonist peptide of any one of claims 1-44, or the pharmaceuticallyacceptable salt thereof, wherein P1 is H.

46. The GIP receptor agonist peptide of any one of claims 1-44, or the pharmaceuticallyacceptable salt thereof wherein P1 is methyl. 59057274.

147. The GIP receptor agonist peptide of any one of claims 1-46, or the pharmaceuticallyacceptable salt thereof, wherein P2 is -NH2.

48. The GIP receptor agonist peptide of any one of claims 1-12, 14-16, 18, 22-24, 29, 30, 33, 34,36, 38, 40, 41, 46 or 47, or the pharmaceutically acceptable salt thereof, wherein A11 is Ser; A13 is Aib or Ala; A14 is Leu or Lys(R); A16 is Arg; A17 is Glu, Gln, or Aib; A21 is Glu, Gln, or Lys(R); A24 is Glu, Asn, Gln, or Lys(R); A26 is Leu; A29 is Gln; A30 is Gly or Arg; and A40 is a deletion; wherein in the residue Lys(R), the (R) portion represents -L-X, wherein L 59057274.1represents a linker and is selected from the group consisting of 2OEGgE, 2OEG2gE, and GGGGG; and X represents C17-C22monoacid or C17-C22diacid.

49. The GIPR agonist peptide of any one of claims 1-31 or 33-48, or the pharmaceuticallyacceptable salt thereof, wherein L is 2OEGgE.

50. The GIP receptor agonist peptide of any one of claims 1-32, 34, or 36-49, or thepharmaceutically acceptable salt thereof, wherein X represents C17-C20 diacid.

51. The GIPR agonist peptide of any one of claims 1-32, 34, or 36-50 wherein X represents C18diacid.

52. The GIP receptor agonist peptide of any one of claims 1-29, 35, 36-38, or 50, or thepharmaceutically acceptable salt thereof, wherein A21 is Lys(R); L is selected from the group consisting of 2OEGgE and 2OEG2gE; and X represents C17-C20 diacid. 59057274.

153. The GIP receptor agonist peptide of any one of claims 1-39, 34, or 36-51, or thepharmaceutically acceptable salt thereof, wherein A21 is Lys(R); L is 2OEGgE; and X represents C18diacid.

54. The GIP receptor agonist peptide of any one of claims 1-53, or the pharmaceuticallyacceptable salt thereof, wherein A40 is a deletion.

55. The GIP receptor agonist peptide of any one of claims 1-12, 17-20, 22-27, 29, 30, 36-47 or54, or the pharmaceutically acceptable salt thereof, wherein the GIP receptor agonist peptide is of Formula (I-B): P1-Tyr-Aib-Glu-Gly-Thr-Val-Val-Ser-Leu-Tyr-Ser-Ile-Aib-Leu-Asp-A16-Glu-A18-Gln- A20-A21-Phe-Val-Asn-Trp-A26-A27-A28-A29-A30-Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser-A40- P2(SEQ ID NO: 15); wherein A21 is Lys(R); 59057274.1wherein in the residue Lys(R), the (R) portion represents -L-X, wherein L represents a linker and is selected from the group consisting of 2OEGgE, 2OEGgEgE, and GGGGG; and X represents C17-C22monoacid or C17-C22diacid; and A40 is a deletion.

56. The GIP receptor agonist peptide of claim 55 wherein A29 is Gly, Gln, or Lys(R).

57. The GIP receptor agonist peptide of claim 55 or 56 wherein A30 is Gly, Arg, Lys or Lys(R).

58. The GIP receptor agonist peptide of any one of claims 55-57 wherein A16 is: Arg or Lys.

59. The GIP receptor agonist peptide of any one of claims 55-58 wherein A18 is: Ala, His, orLys(R).

60. The GIP receptor agonist peptide of any one of claims 55-59 wherein A20 is: Aib, Lys, orLys(R). 59057274.

161. The GIP receptor agonist peptide of any one of claims 55-60 wherein A21 is: Glu, Asn, Asp,Lys, Gln, or Lys(R).

62. The GIP receptor agonist peptide of any one of claims 55-61 wherein A26 is: Leu or Iva.

63. The GIP receptor agonist peptide of any one of claims 55-62 wherein A27 is: Leu or Ala.

64. The GIP receptor agonist peptide of any one of claims 55-63 wherein A28 is: Ala or Lys.

65. The GIP receptor agonist peptide of any one of claims 55-64 wherein A29 is: Gly, Gln, orLys(R).

66. The GIP receptor agonist peptide of any one of claims 55-65 wherein A30 is: Glu, Gly, Arg,Lys, or Lys(R). 59057274.

167. The GIP receptor agonist peptide of any one of claims 1-66, or the pharmaceuticallyacceptable salt thereof, wherein the GIP receptor agonist peptide has at least three unnatural amino acids.

68. The GIP receptor agonist peptide of any one of claims 1-67, or the pharmaceuticallyacceptable salt thereof, wherein the GIP receptor agonist peptide has three unnatural amino acids.

69. The GIP receptor agonist peptide of claim 68, or the pharmaceutically acceptable salt thereof,wherein the three unnatural amino acids are each Aib.

70. The GIP receptor agonist peptide of any one of claims 1-69, or the pharmaceuticallyacceptable salt thereof, wherein the GIP receptor agonist peptide has at least 32 amino acid residues.

71. The GIP receptor agonist peptide of any one of claims 1-70, or the pharmaceuticallyacceptable salt thereof, wherein the GIP receptor agonist peptide has 32-40 amino acid residues. 59057274.

172. The GIP receptor agonist peptide of any one of claims 1-71, or the pharmaceuticallyacceptable salt thereof, wherein the GIP receptor agonist peptide has 39 amino acid residues.

73. The GIP receptor agonist peptide of any one of claims 1-72, or the pharmaceuticallyacceptable salt thereof, wherein the GIP receptor agonist peptide is: H-Tyr-Aib-Glu-Gly-Thr-Val-Val-Ser-Leu-Tyr-Ser-Ile-Aib-Lys(R)-Asp-Arg-Glu- Ala-Gln-Aib-Glu-Phe-Val-Asn-Trp-Leu-Leu-Ala-Gln-Arg-Pro-Ser-Ser-Gly-Ala-Pro-Pro- Pro-Ser-NH2; and Lys(R) is 2OEGgE-C17 diacid.

74. The GIP receptor agonist peptide of any one of claims 1-72, or the pharmaceuticallyacceptable salt thereof, wherein the GIP receptor agonist peptide is: H-Tyr-Aib-Glu-Gly-Thr-Val-Val-Ser-Leu-Tyr-Ser-Ile-Aib-Leu-Asp-Arg-Glu-Ala-Gln-Aib- Lys(R)-Phe-Val-Asn-Trp-Leu-Leu-Ala-Gln-Arg-Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser-NH2; and Lys(R) is 2OEGgE-C18 diacid.

75. The GIP receptor agonist peptide of any one of claims 1-72, or the pharmaceuticallyacceptable salt thereof, wherein the GIP receptor agonist peptide is: 59057274.1H-Tyr-Aib-Glu-Gly-Thr-Val-Val-Ser-Leu-Tyr-Ser-Ile-Aib-Leu-Asp-Arg-Glu-Ala-Gln-Aib- Lys(R)-Phe-Val-Asn-Trp-Leu-Leu-Ala-Gln-Arg-Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser-NH2; and Lys(R) is 2OEGgE-C17monoacid.

76. The GIP receptor agonist peptide of any one of claims 1-72, or the pharmaceuticallyacceptable salt thereof, wherein the GIP receptor agonist peptide is: H-Tyr-Aib-Glu-Gly-Thr-Val-Val-Ser-Leu-Tyr-Ser-Ile-Aib-Leu-Asp-Arg-Glu-Ala-Gln-Aib- Lys(R)-Phe-Val-Glu-Trp-Leu-Leu-Ala-Gln-Arg-Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser-NH2; and Lys(R) is 2OEGgE-C18diacid.

77. The GIP receptor agonist peptide of any one of claims 1-76, or the pharmaceuticallyacceptable salt thereof, wherein the GIP receptor agonist peptide has a selectivity ratio, expressed as a ratio of (GLP1R EC50 / GIPR EC50) of greater than 10, or greater than 100, or greater than 1,000, greater than 10,000, or greater than 100,000. 59057274.

178. The GIP receptor agonist peptide of any one of claims 1-77, or the pharmaceuticallyacceptable salt thereof, wherein the GIP receptor agonist peptide has an IV half life of elimination of greater than about 50 hours.

79. The GIP receptor agonist peptide of any one of claims 1-78, or the pharmaceuticallyacceptable salt thereof, wherein the GIP receptor agonist peptide has a solubility of 15 mg / mL or greater at pH 7.4.

80. The GIP receptor agonist peptide of any one of claims 1-79, or the pharmaceuticallyacceptable salt thereof, wherein the GIP receptor agonist peptide has a solubility of 30 mg / mL or greater at pH 7.4.

81. A medicament comprising the GIP receptor agonist peptide of any one of claims 1-80, or apharmaceutically acceptable salt thereof.

82. The medicament of claim 81, which is an activator of a GIP receptor.59057274.

183. The medicament of claim 81or 82, which is a suppressant for vomiting or nausea.

84. A pharmaceutical composition comprising the GIP receptor agonist peptide of any one ofclaims 1-83, or a pharmaceutically acceptable salt thereof.

85. The GIP receptor agonist peptide of any one of claims 1-80, or a pharmaceutically acceptablesalt thereof, or the medicament of any one of claims 81-83, or the pharmaceutical composition of claim 86, which is administered to treat emesis as a monotherapy.

86. The GIP receptor agonist peptide of any one of claims 1-80, or a pharmaceutically acceptablesalt thereof, or the medicament of any one of claims 81-83, or the pharmaceutical composition of claim 84, which is administered to a subject Q1W, once per four to seven days, or once per four to five days, or once every four days, or once every five days, or once every six days, or once every seven days, or once everyeight days, or once every nine days, or once every ten days, to treat or prevent emesis, including vomiting and / or nausea. 59057274.

187. The GIP receptor agonist peptide of any one of claims 1-80, or a pharmaceutically acceptablesalt thereof, or the medicament of any one of claims 81-83, or the pharmaceutical composition of claim 84, for use in suppressing vomiting or nausea.

88. Use of the GIP receptor agonist peptide of any one of claims 1-80, or a pharmaceuticallyacceptable salt thereof, or the medicament of any one of claims 81-82, or the pharmaceutical composition of claim 84, for the manufacture of a suppressant for vomiting or nausea.

89. A method of activating of a GIP receptor, the method comprising administering a GIPreceptor agonist peptide of any one of claims 1-80.

90. A method of preventing or treating emesis in a subject, comprising administering to thesubject an effective amount of the GIP receptor agonist peptide of any one of claims 1-80, or a pharmaceutically acceptable salt thereof, or the medicament of any one of claims 81-83, or the pharmaceutical composition of claim 84.

91. The method of claim 90, wherein the emesis is nausea and / or vomiting.59057274.

192. The method of claim 90 or 91, wherein the method comprises activating of a GIP receptor.

93. The GIP receptor agonist peptide of any one of claims 1-80, or a pharmaceutically acceptablesalt thereof, or the medicament of any one of claims 81-82, or the pharmaceutical composition of claim 84, or the method of any one of claims 89-92 where the emesis, vomiting, or the nausea is caused by one or more conditions or causes selected from the following group consisting of options (1) to (10): (1) Diseases accompanied by vomiting or nausea including gastroparesis, gastrointestinal hypomotility, peritonitis, abdominal tumor, constipation, gastrointestinal obstruction, chronic intestinal pseudo-obstruction, functional dyspepsia, cyclic vomiting syndrome, chronic unexplained nausea and vomiting, acute pancreatitis, chronic pancreatitis, hepatitis, hyperkalemia, cerebral edema, intracranial lesion, metabolic disorder, gastritis caused by an infection, postoperative disease, myocardial infarction, migraine, intracranial hypertension, and intracranial hypotension or altitude sickness; (2) Vomiting and / or nausea induced by chemotherapeutic drugs including (i) alkylating agents or cyclophosphamide, carmustine, lomustine, chlorambucil, streptozocin, dacarbazine, 59057274.1ifosfamide, temozolomide, busulfan, bendamustine, or melphalan, cytotoxic antibiotics or dactinomycin, doxorubicin, mitomycin-C, bleomycin, epirubicin, actinomycin D, amrubicin, idarubicin, daunorubicin, or pirarubicin), antimetabolic agents or cytarabine, methotrexate, 5- fluorouracil, enocitabine, or clofarabine), vinca alkaloids or etoposide, vinblastine, or vincristine), chemotherapeutic agents including cisplatin, procarbazine, hydroxyurea, azacytidine, irinotecan, interferon α, interleukin-2, oxaliplatin, carboplatin, nedaplatin, or miriplatin; (ii) opioid analgesics or morphine; (iii) dopamine receptor D1D2 agonists or apomorphine; (iv) cannabis and cannabinoid products including cannabis hyperemesis syndrome; (3) Vomiting or nausea caused by radiation sickness or radiation therapy for the chest, or the abdomen used to treat cancers; (4) Vomiting or nausea caused by a poisonous substance or a toxin; (5) Vomiting and nausea caused by pregnancy including hyperemesis gravidarium; and (6) Vomiting and nausea caused by a vestibular disorder such as motion sickness or dizziness (7) Opioid withdrawal; (8) A vestibular disorder such as motion sickness or dizziness; and (9) A physical injury causing local, systemic, acute or chronic pain. 59057274.

194. The method of any one of claims 89-93, wherein the emesis is a result of cyclic vomitingsyndrome or chemotherapy.

95. The method of any one of claims 89-94, wherein the subject is a non-type 2 diabetes mellitussubject.

96. The method of any one of claims 89-95, wherein the emesis is delayed emesis or anticipatoryemesis.

97. The method of any one of claims 89-96, wherein the emesis is treated in the subject withoutinducing suppression of glucagon secretion when plasma glucose levels are above fasting levels.

98. The method of any one of claims 89-97, wherein the emesis is treated in the subject withoutsubstantially activating the GLP-1 receptor. 59057274.

199. The method of any one of claims 89-98, wherein the emesis is treated in the subject withoutconcomitant, subsequent, or prior administration of a GLP-1 receptor agonist.

100. The method of any one of claims 89-99, wherein the emesis is treated in a subject not takinga medicament to control a metabolic syndrome disorder.

101. The method of any one of claims 89-100, wherein the emesis is treated in a subject taking amedicament to control a metabolic syndrome disorder.

102. The method of claim 101, wherein the metabolic syndrome disorder is type 2 diabetesmellitus or obesity.

103. The method of any one of claims 89-102, wherein the emesis is caused by or causes cyclicvomiting syndrome, or nausea or vomiting associated with chemotherapy.

104. The method of claim 94 or claim 103, wherein the chemotherapy or chemotherapeutic agentcomprises: (i) alkylating agents or cyclophosphamide, carmustine, lomustine, chlorambucil, 59057274.1streptozocin, dacarbazine, ifosfamide, temozolomide, busulfan, bendamustine, or melphalan), cytotoxic antibiotics or dactinomycin, doxorubicin, mitomycin-C, bleomycin, epirubicin, actinomycin D, amrubicin, idarubicin, daunorubicin, or pirarubicin, antimetabolic agents or cytarabine, methotrexate, 5-fluorouracil, enocitabine, or clofarabine, vinca alkaloids or etoposide, vinblastine, and vincristine, chemotherapeutic agents including cisplatin, procarbazine, hydroxyurea, azacytidine, irinotecan, interferon α, interleukin-2, oxaliplatin, carboplatin, nedaplatin, or miriplatin; (ii) opioid analgesics or morphine; (iii) dopamine receptor D1D2 agonists or apomorphine; or (iv) cannabis and cannabinoid products including cannabis hyperemesis syndrome.

105. The method of any one of claims 89-104, wherein the subject has type 2 diabetes mellitus.

106. The method of any one of claims 89-105, wherein the GIP receptor agonist peptide ormedicament is administered subcutaneously, intravenously, intramuscularly, intraperitonealy, orally or via inhalation.

107. The method of any one of claims 89-106, wherein the GIP receptor agonist peptide ormedicament is administered subcutaneously. 59057274.1108. The method of any one of claims 89-107, wherein the effective amount of the GIP receptoragonist peptide administered to the subject is about 0.01 to 0.5 mg / kg / day, 0.1 to 5 mg / kg / day, 5 to 10 mg / kg / day, 10 to 20 mg / kg / day, 20 to 50 mg / kg / day, 10 to 100 mg / kg / day, 10 to 120 mg / kg / day, 50 to 100 mg / kg / day, 100 to 200 mg / kg / day, 200 to 300 mg / kg / day, 300 to 400 mg / kg / day, 400 to 500 mg / kg / day, 500 to 600 mg / kg / day, 600 to 700 mg / kg / day, 700 to 800 mg / kg / day, 800 to 900 mg / kg / day, or 900 to 1000 mg / kg / day.

109. The method of any one of claims 89-109, wherein the subject is human.

110. The method of any one of claims 89-109, wherein the GIP receptor agonist peptide ormedicament is administered to the subject before, during, or after the subject develops the emesis, the vomiting, the nausea, or the one or more conditions or causes of claim 67.

111. The method of any one of claims 89-110, wherein the GIP receptor agonist peptide ormedicament is administered to the subject once per week, or once per 5-7 days, or four to six times per month. 59057274.1112. The method of any one of claims 89-111, wherein the GIP receptor agonist peptide ormedicament is administered to the subject for 1-5 days, 1-5 weeks, 1-5 months, or 1-5 years.

113. The method according to any one of claims 89-110, 111, or 112, wherein the GIP receptor agonist peptide or medicament is administered to the subject once per week. 59057274.1

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