GIP receptor agonist peptide compounds and uses thereof

Abstract

To provide a GIP receptor agonist peptide compound having an activating action on a GIP receptor.SOLUTION: To provide a new peptide compound containing an amino acid sequence represented by a specific sequence and having activation action on a GIP receptor, and to provide use of the peptide compound as a medicine.SELECTED DRAWING: None

Description

[Technical Field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims priority to U.S. Provisional Application No. 62 / 735,548, filed September 24, 2018, which is incorporated herein by reference in its entirety.

[0002] The present disclosure relates to novel peptide compounds that have activating activity on the GIP receptor and the use of the peptide compounds as pharmaceuticals. [Background technology]

[0003] The statements in this section merely provide background information related to the present disclosure and may not constitute prior art.

[0004] Glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) are both peptides called incretins. GLP-1 and GIP are secreted by L and K cells, respectively, in the small intestine.

[0005] GLP-1 is known to act via the GLP-1 receptor to stimulate glucose-dependent insulin secretion and suppress appetite, while GIP is known to stimulate glucose-dependent insulin secretion via the GIP receptor, but its effect on feeding alone is unclear.

[0006] Attempts have been made to search for peptides with GLP-1 receptor / GIP receptor co-agonist or glucagon receptor / GLP-1 receptor / GIP receptor triagonist activity and modifications thereof, and to develop these peptides as anti-obesity drugs, diabetes treatment drugs, or neurodegenerative disorder treatment drugs based on the structure of native glucagon, GIP, or GLP-1. However, no peptide compounds or compounds having selective activating activity against the GIP receptor of the present disclosure have been disclosed for use in treating vomiting and similar symptoms associated with vomiting, such as nausea and vomiting.

[0007] All publications, patents, and patent applications cited herein are hereby incorporated by reference in their entirety. Summary of the Invention

[0008] An object of the present invention is to provide a GIP receptor agonist peptide compound which has a GIP receptor activating effect and is useful as a prophylactic / therapeutic agent for diabetes and obesity, and / or an antiemetic agent for the prophylaxis / treatment of diseases accompanied by vomiting or nausea.

[0009] The present disclosure provides extensive research to solve the above-mentioned problems and has discovered GIP agonist peptide compounds having sequences represented by formulas (I) to (VIII) as compounds having excellent GIP receptor activating activity. Furthermore, the present disclosure provides GIP agonist compounds that selectively activate GIP receptors, have antiemetic activity, and are used to treat and / or prevent emesis in vivo.

[0010] The present disclosure provides extensive research to solve the above-mentioned problems, and has discovered peptide compounds having sequences represented by formulas (I) to (VIII) as novel compounds having excellent GIP receptor activating activity. Furthermore, the present disclosure provides experimental support for demonstrating that these GIP agonist peptides selectively activate GIP receptors and have antiemetic activity. do.

[0011] More specifically, the present disclosure includes the following embodiments (1) to (19).

[0012] (1). Formula (I): P 1 -A1-A2-A3-A4-A5-A6-A7-A8-A9-A10-A11-A12-A13-A14-A15-A16-A17-A18-A19-A20-A21-A2 2-A23-A24-A25-A26-A27-A28-A29-A30-A31-A32-A33-A34-A35-A36-A37-A38-A39-A40-A41-P2 A GIP receptor agonist peptide represented by (SEQ ID NO: 4), or a salt thereof, During the ceremony, P 1 teeth, -R A1 , -CO-R A1 , -CO-OR A1 , -CO-COR A1 , -SO-R A1 , -SO2-R A1 , -SO2-OR A1 , -CO-NR A2 R A3 , -SO2-NR A2 R A3 , -C(=NR A1 )-NR A2 R A3 or represents a group of the formula Does not exist, R A1 , R A2 , and R A3 each independently represents a hydrogen atom, an optionally substituted hydrocarbon group, or an optionally substituted heterocyclic group; P 2 represents -NH2 or -OH, A1 represents Tyr, 3,5-Dix Tyr, D-Tyr, 3,5 di-Br-Tyr, Phe, alpha methyl-Phe, mono-halo-Phe, bis-halo-Phe, -Tyr, -D-Phe, -D-Tyr, des-amino-Phe, or des-amino-Tyr; A2 represents Aib, Ala, Gly, Sar, Abu, or D-Ala; A3 represents Glu or Pro, A4 represents Gly or Ser, A5 represents Thr, D-Iva, Glu, Iva, or Ser; A6 represents Ala, Aib, alpha-methyl-Phe, A6C, Glu, Iva, Arg, Phe, or Val; A7 represents Ile, Lys, Val, Ala, Aib, α-methyl-Leu, A6C, Asp, Phe, Gly, Iva, Leu, Arg, or Ser; A8 represents Ser, Ala, Aib, Asp, Phe, Gly, Leu, or Arg; A9 represents Asp, Leu, Aib, Glu, Asn, Gln, Ser, or Phe; A10 represents Aib, α-methyl-Phe, A6C, Lys, or Tyr; A11 represents Aib Ser, Ala, Glu, Iva, A5c, A6c, or Leu; A12 represents Ile, Ala, Aib, Glu, α-methyl-Phe, Phe, Lys, Arg, Ser, Trp, A6C, Cys, or Asp; A13 represents Aib, Ala, Val, Iva, Gln, Leu, Tyr, D-Iva, alpha methyl-Phe, A6C, or Glu; A14 represents Leu, Nle, Tyr, Ala, Aib, α-methyl-Leu, Lys, Leu, Ser, Met, or Me; A15 represents Ala, Aib, Leu, Asn, Asp, Glu, Lys, Ser, or Tyr; A16 represents Arg, Ala, Aib, Glu, Gly, Leu, Ser, or Lys; A17 represents Aib, Ala, Lys, Asp, Arg, Gln, Glu, or Ile; A18 represents Ala, Aib, A6C, Phe, Gly, Iva, Leu, Ser, Trp, or His; A19 represents Gln, Ala, Val, Aib, Ile, Arg, or Ser; A20 represents Aib, Ala, Arg, Glu, Gly, Ser, Val, or Gln; A21 represents Asn, Asp, Glu, Leu, Ala, Aib, Lys, Gln, or Ser; A22 represents Phe, Glu, Gln, Arg, Trp, or αMePhe; A23 represents Ile, Aib, Asp, Glu, Arg, Thr, or Val; A24 represents Arg, Asn, Asp, Lys, Lys(Ac), Ala, Aib, Cys, Phe, Leu, Nle, Ser, Asp, or Gln; A25 represents Trp, Aib, α-methyl-Leu, A6C, Ile, Asn, Nle, Arg, or Val; A26 represents Aib, Iva, Ala, alpha-methyl-Leu, A6C, Ile, Asn, Nle, Arg, Val, or Leu; A27 represents Leu, Val, Ala, Aib, alpha-methyl-Leu, A6C, Ile, Met, Nle, Arg, Trp, or Ile; A28 represents Ala, Arg, Lys, Aib, Asp, Asn, or Lys(Ac); A29 represents Gln, Gly, Arg, Glu, Leu, or Aib; A30 represents Lys, Arg, Gly, or Glu; A31 represents Pro, Gly, Hyp, Gln, Phe, ψ, or a deletion; A32 represents Ser, Gly, Arg, Lys, ψ, or a deletion; A33 represents Ser, Gly, Pro, Lys, ψ, or a deletion; A34 represents Gly, Ser, Asn, ψ, or a deletion; A35 represents Ala, Ser, Ser, Asp, ψ, or a deletion; A36 represents Pro, Gly, Gly, Hyp, Trp, ψ, or a deletion; A37 represents Pro, Gly, Ala, Hyp, Lys, ψ, or a deletion; A38 represents Pro, Gly, Hyp, His, ψ, or a deletion; A39 represents Ser, Gly, Lys, Pro, Asn, ψ, or a deletion; A40 represents Arg, Ser, Cys, Glu, Lys, Lys-Ac, Pro, Ile, ψ, or a deletion; A41 represents Gly, Ser, Ile, Thr, ψ, or a deletion; Any one or two amino acids selected from A31 to A41 optionally represent ψ, where ψ is a residue independently selected from Lys, Arg, Orn, and Cys, and the side chain of the residue is substituted, provided that the GIP receptor agonist peptide is not a peptide having any one of the amino acid sequences of SEQ ID NOs: 4 to 569 disclosed in PCT / JP2018 / 013540. The GIP receptor agonist peptide or a salt thereof.

[0013] (2).Formula (II): P 1 -Tyr-A2-Glu-Gly-Thr-A6-A7-A8-A9-A10-A1 1-A12-A13-A14-A15-A16-A17-A18-A19-A20-A21-A22-A23-A24-A25-A26 -A27-A28-A29-A30-A31-A32-A33-A34-A35-A36-A37-A38-A39-A40-A41-P 2 (SEQ ID NO: 5) or a salt thereof, wherein: P 1 teeth, -R A1 , -CO-R A1 , -CO-OR A1 , -CO-COR A1 , -SO-R A1 , -SO2-R A1 , -SO2-OR A1 , -CO-NR A2 R A3 , -SO2-NR A2 R A3,or -C(=NR A1 )-NR A2 R A3 represents a group represented by the formula: R A1 , R A2 , and R A3 each independently represents a hydrogen atom, an optionally substituted hydrocarbon group, or an optionally substituted heterocyclic group; P 2 represents -NH2 or -OH, A2 represents Aib or D-Ala; A6 represents Iva, Phe, or Val; A7 represents Ile, Lys, or Val; A8 represents Ser, A9 represents Asp, Leu, or Phe; A10 represents Tyr, A11 represents Aib or Ser; A12 represents Ile, A13 represents Aib, Ala, Gln, Leu, Tyr, or D-Iva; A14 represents Leu, A15 represents Asp, Glu, Lys, Ser, or Tyr; A16 represents Arg or Lys; A17 represents Aib, Gln, or Ile; A18 represents Ala or His; A19 represents Gln or Ser; A20 represents Aib, Ala, or Gln; A21 represents Asn, Asp, Glu, Leu, or Ser; A22 represents Phe or αMePhe; A23 represents Ile or Val, A24 represents Arg, Asn, Asp, Lys, or Lys(Ac); A25 represents Trp, A26 stands for Aib, Iva, or Leu, A27 represents Leu, A28 represents Ala, Arg, Lys, or Lys(Ac); A29 represents Gln or Gly; A30 represents Arg or Gly; A31 represents Pro, Gly, ψ, or a deletion; A32 represents Ser, Gly, ψ, or a deletion; A33 represents Ser, Gly, ψ, or a deletion; A34 represents Gly, ψ, or a deletion; A35 represents Ala, Ser, ψ, or a deletion; A36 represents Pro, Gly, ψ, or a deletion; A37 represents Pro, Gly, ψ, or a deletion; A38 represents Pro, Gly, ψ, or a deletion; A39 represents Ser, Gly, ψ, or a deletion; A40 represents Arg, Ser, ψ, or a deletion; A41 represents Gly, ψ, or a deletion; The GIP receptor agonist peptide or a salt thereof, wherein any one or two amino acids selected from A31 to A41 optionally represent ψ, where ψ is a residue independently selected from Lys, Arg, Orn, and Cys, and the side chain of the residue is substituted, provided that the GIP receptor agonist peptide is not a peptide having any one of the amino acid sequences of SEQ ID NOs: 4 to 569 disclosed in PCT / JP2018 / 013540.

[0014] (3).Formula (III): P 1 -Tyr-A2-Glu-Gly-Thr-A6-A7-A8-A9-A10-A11-A12-A13-A14-A15-A16-A17-A18-A19-A20-A21- A22-A23-A24-A25-A26-A27-A28-A29-A30-A31-A32-A33-A34-A35-A36-A37-A38-A39-A40-A41-P 2(SEQ ID NO: 6) or a salt thereof, wherein: P 1 teeth, -R A1 , -CO-R A1 , -CO-OR A1 , -CO-COR A1 , -SO-R A1 , -SO2-R A1 , -SO2-OR A1 , -CO-NR A2 R A3 , -SO2-NR A2 R A3 ,or -C(=NR A1 )-NR A2 R A3 represents a group represented by the formula: R A1 , R A2 , and R A3 each independently represents a hydrogen atom, an optionally substituted hydrocarbon group, or an optionally substituted heterocyclic group; P 2 represents -NH2 or -OH, A2 represents Aib or D-Ala; A6 represents Iva, Phe, or Val; A7 represents Ile, Lys, or Val; A8 represents Ser, A9 represents Asp, Leu, or Phe; A10 represents Tyr, A11 represents Aib or Ser; A12 represents Ile, A13 represents Aib, Ala, Gln, Leu, Tyr, or D-Iva; A14 represents Leu, A15 represents Asp, Glu, Lys, Ser, or Tyr; A16 represents Arg or Lys; A17 represents Aib, Gln, or Ile; A18 represents Ala or His; A19 represents Gln or Ser; A20 represents Aib, Ala, or Gln; A21 represents Asn, Asp, Glu, Leu, or Ser; A22 represents Phe or αMePhe; A23 represents Ile or Val, A24 represents Arg, Asn, Asp, Lys, or Lys(Ac); A25 represents Trp, A26 stands for Aib, Iva, or Leu, A27 represents Leu, A28 represents Ala, Arg, Lys, or Lys(Ac); A29 represents Gln or Gly; A30 represents Arg or Gly; A31 represents Pro, Gly, ψ, or a deletion; A32 represents Ser, Gly, ψ, or a deletion; A33 represents Ser, Gly, ψ, or a deletion; A34 represents Gly, ψ, or a deletion; A35 represents Ala, Ser, ψ, or a deletion; A36 represents Pro, Gly, ψ, or a deletion; A37 represents Pro, Gly, ψ, or a deletion; A38 represents Pro, Gly, ψ, or a deletion; A39 represents Ser, Gly, ψ, or a deletion; A40 represents Arg, Ser, ψ, or a deletion; A41 represents Gly, ψ, or a deletion; Any one or two amino acids selected from A31 to A41 optionally represent ψ, where ψ is a residue independently selected from Lys, Arg, Orn, and Cys, and the side chain of the residue is substituted, provided that the GIP receptor agonist peptide is not a peptide having any one of the amino acid sequences of SEQ ID NOs: 4 to 569 disclosed in PCT / JP2018 / 013540. The GIP receptor agonist peptide or a salt thereof.

[0015] (4).Formula (IV): P 1 -A1-A2-Glu-Gly-Thr-A6-A7-A8-A9-A10-A11-A12-A13-A14-A15-A16-A17-A18-A19-A20-A21-A 22-A23-A24-A25-A26-A27-A28-A29-A30-A31-A32-A33-A34-A35-A36-A37-A38-A39-A40-A41-P 2 (SEQ ID NO: 7) or a salt thereof, wherein: P 1 teeth, -R A1 , -CO-R A1 , -CO-OR A1 , -CO-COR A1 , -SO-R A1 , -SO2-R A1 , -SO2-OR A1 , -CO-NR A2 R A3 , -SO2-NR A2 R A3 ,or -C(=NR A1 )-NR A2 R A3 represents a group represented by the formula: R A1 , RA2 , and R A3 are each independently a hydrogen atom, an optionally substituted represents a hydrocarbon group or an optionally substituted heterocyclic group; P 2 represents -NH2 or -OH, A1 represents Tyr, A2 represents Aib or D-Ala; A6 represents Iva, Phe, or Val; A7 represents Ile, Lys, or Val; A8 represents Ser, A9 represents Asp, Leu, or Phe; A10 represents Tyr, A11 represents Aib or Ser; A12 represents Ile, A13 represents Aib, Ala, Gln, Leu, Tyr, or D-Iva; A14 represents Leu, A15 represents Asp, Glu, Lys, Ser, or Tyr; A16 represents Arg or Lys; A17 represents Aib, Gln, or Ile; A18 represents Ala or His; A19 represents Gln or Ser; A20 represents Aib, Ala, or Gln; A21 represents Asn, Asp, Glu, Leu, or Ser; A22 represents Phe or αMePhe; A23 represents Ile or Val, A24 represents Arg, Asn, Asp, Lys, or Lys(Ac); A25 represents Trp, A26 stands for Aib, Iva, or Leu, A27 represents Leu, A28 represents Ala, Arg, Lys, or Lys(Ac); A29 represents Gln or Gly; A30 represents Arg, A31 represents Pro, Gly, ψ, or a deletion; A32 represents Ser, Gly, ψ, or a deletion; A33 represents Ser, Gly, ψ, or a deletion; A34 represents Gly, ψ, or a deletion; A35 represents Ala, Ser, ψ, or a deletion; A36 represents Pro, Gly, ψ, or a deletion; A37 represents Pro, Gly, ψ, or a deletion; A38 represents Pro, Gly, ψ, or a deletion; A39 represents Ser, Gly, ψ, or a deletion; A40 represents Arg, Ser, ψ, or a deletion; A41 represents Gly, ψ, or a deletion; Any one or two amino acids selected from A31 to A41 optionally represent ψ, where ψ is a residue independently selected from Lys, Arg, Orn, and Cys, and the side chain of the residue is substituted, provided that the GIP receptor agonist peptide is not a peptide having any one of the amino acid sequences of SEQ ID NOs: 4 to 569 disclosed in PCT / JP2018 / 013540. The GIP receptor agonist peptide or a salt thereof.

[0016] (5).A1-A2-Glu-Gly-Thr-A6-A7-A8-A9-A10-A11-A12-A13-A14-A15-A16-A17-A18-A19-A20-A21-A22-A23-A24-A25-A26-A27-A28-A2 in formula (I) 9 is Tyr-Aib-Glu-Gly-Thr-Phe-Ile-Ser-Asp-Tyr-Ser-Ile-Ala-Leu-Asp-Arg-Aib-His-Gln-Aib-Asn-Phe-Val-Asn-Trp-Iva-Leu-Ala-Gln (SEQ ID NO: 8), A GIP receptor agonist peptide according to (1), represented by formula (V), or a salt thereof, provided that the GIP receptor agonist peptide is not a peptide having any one of the amino acid sequences of SEQ ID NOs: 4 to 569 disclosed in PCT / JP2018 / 013540. The GIP receptor agonist peptide or a salt thereof.

[0017] (6). Formula (VI): P 1 -Tyr-Aib-Glu-Gly-Thr-Phe-Ile-Ser-Asp-Tyr-Ser-Ile-Ala-Leu-Asp-Arg-Aib-His-Gln-Aib-As n-Phe-Val-Asn-Trp-Iva-Leu-Ala-Gln-A30-A31-A32-A33-A34-A35-A36-A37-A38-A39-A40-A41-P 2 (SEQ ID NO: 9) or a salt thereof, During the ceremony, P 1 teeth, -R A1 , -CO-R A1 , -CO-OR A1 , -CO-COR A1 , -SO-R A1 , -SO2-R A1 , -SO2-OR A1 , -CO-NR A2 R A3 , -SO2-NR A2 R A3 ,or -C(=NR A1 )-NR A2 R A3 represents a group represented by the formula: R A1 , R A2 , and R A3each independently represents a hydrogen atom, an optionally substituted hydrocarbon group, or an optionally substituted heterocyclic group; P 2 represents -NH2 or -OH, A30 represents Arg, A31 represents Pro, Gly, or Lys(R); A32 represents Ser, Gly, or Lys(R); A33 represents Ser, Gly, or Lys(R); A34 represents Gly or Lys(R), A35 represents Ala, Ser, or Lys(R); A36 represents Pro, Gly, or Lys(R); A37 represents Pro, Gly, Lys(R), or a deletion; A38 represents Pro, Gly, Lys(R), or a deletion; A39 represents Ser, Gly, Lys(R), or a deletion; A40 represents Arg, Ser, Lys(R), or a deletion; A41 represents Gly, Lys(R), or a deletion; Any one or two amino acids selected from A31 to A41 optionally represent Lys(R), where (R) represents a substituent, provided that the GIP receptor agonist peptide is not a peptide having any one of the amino acid sequences of SEQ ID NOs: 4 to 569 disclosed in PCT / JP2018 / 013540. The GIP receptor agonist peptide or a salt thereof.

[0018] (7).Formula (VII): P 1 -Tyr-Aib-Glu-Gly-Thr-Phe-Ile-Ser-Asp-Tyr-Ser-Ile-Ala-Leu-Asp-Arg-Aib-His-Gln-Ai b-Asn-Phe-Val-Asn-Trp-Iva-Leu-Ala-Gln-A30-A31-A32-A33-A34-A35-A36-A37-A38-A39-P2 (SEQ ID NO: 10) or a salt thereof, wherein: P 1 teeth, -R A1 , -CO-R A1 , -CO-OR A1 , -CO-COR A1 , -SO-R A1 , -SO2-R A1 , -SO2-OR A1 , -CO-NR A2 R A3 , -SO2-NR A2 R A3 ,or -C(=NR A1 )-NR A2 R A3 represents a group represented by the formula: R A1 , R A2 , and R A3 each independently represents a hydrogen atom, an optionally substituted hydrocarbon group, or an optionally substituted heterocyclic group; P 2 represents -NH2 or -OH, A30 represents Arg, A31 represents Pro, Gly, or Lys(R); A32 represents Ser, Gly, or Lys(R); A33 represents Ser, Gly, or Lys(R); A34 represents Gly or Lys(R), A35 represents Ala, Ser, or Lys(R); A36 represents Pro, Gly, or Lys(R); A37 represents Pro, Gly, Lys(R), A38 represents Pro, Gly, Lys(R), A39 represents Ser, Gly, or Lys(R); wherein any one or two amino acids selected from A31 to A39 optionally represent Lys(R), where (R) represents a substituent or a salt thereof; The GIP receptor agonist peptide or a salt thereof.

[0019] (8).Formula (VIII): P 1 -Tyr-Aib-Glu-Gly-Thr-Phe-Ile-Ser-Asp-Tyr-Ser-Ile-Ala-Leu-Asp-Arg-Aib-His-Gln-Aib- Asn-Phe-Val-Asn-Trp-Iva-Leu-Ala-Gln-A30-A31-A32-A33-A34-A35-A36-A37-A38-A39-A40-P 2 (SEQ ID NO: 11) or a salt thereof, wherein: P 1 teeth, -R A1 , -CO-R A1 , -CO-OR A1 , -CO-COR A1 , -SO-R A1 , -SO2-R A1 , -SO2-OR A1 , -CO-NR A2 R A3 , -SO2-NR A2 R A3 ,or -C(=NR A1 )-NR A2 R A3 represents a group represented by the formula: R A1 , R A2 , and R A3each independently represents a hydrogen atom, an optionally substituted hydrocarbon group, or an optionally substituted heterocyclic group; P 2 represents -NH2 and -OH, A30 represents Arg, A31 represents Pro, Gly, or Lys(R); A32 represents Ser, Gly, or Lys(R); A33 represents Ser, Gly, or Lys(R); A34 represents Gly or Lys(R), A35 represents Ala, Ser, or Lys(R); A36 represents Pro or Lys(R); A37 represents Pro or Lys(R); A38 represents Pro or Lys(R); A39 represents Ser or Lys(R); A40 represents Arg or Ser; wherein any one or two amino acids selected from A31 to A39 optionally represent Lys(R), where (R) represents a substituent or a salt thereof; The GIP receptor agonist peptide or a salt thereof.

[0020] (9) The GIP receptor agonist peptide according to (1), wherein ψ is a residue independently selected from Lys, Arg, Orn, and Cys, and the side chain of the residue is substituted.

[0021] (10) The GIP receptor agonist peptide of (9), wherein ψ is a residue independently selected from Lys, Arg, Orn, and Cys, and the side chain of said residue is substituted with XL-. In various embodiments, L represents a bond or a divalent substituent, and X represents an optionally substituted hydrocarbon group or a salt thereof.

[0022] (11) The GIP receptor agonist peptide has a molecular weight of more than 10, or more than 100, or more than 1,000, or more than 100,000 (GLP1R EC 50 / GIPR EC 50 The GIP receptor agonist peptide according to (1), having a selective ratio expressed as a ratio of (1 / 2).

[0023] (12) The GIP receptor agonist peptide according to (1), wherein vomiting is treated as a monotherapy by administering the GIP receptor agonist peptide or a medicine containing the GIP receptor agonist peptide, or a pharmaceutical composition containing the GIP receptor agonist peptide.

[0024] (13) A pharmaceutical comprising the GIP receptor agonist peptide or a salt thereof according to (1).

[0025] (14) Use of the GIP receptor agonist peptide or a salt thereof according to (1) for the manufacture of an antiemetic or antinausea agent.

[0026] (15) The peptide or salt thereof according to (1) for use in suppressing vomiting or nausea.

[0027] (16) A method for preventing or treating vomiting in a subject, comprising administering to the subject an effective amount of the peptide of (1) or a salt thereof.

[0028] (17) The pharmaceutical composition according to (13), the use according to (14), the peptide according to (15), and the method according to (16), wherein the vomiting, emesis, or nausea is caused by one or more conditions or causes selected from the following (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 due to infection, postoperative disease, myocardial infarction, migraine, intracranial hypertension, and intracranial hypotension (e.g., altitude sickness), (2)(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), metabolic inhibitors (e.g., cytarabine, methotrexate, 5-fluorouracil, enocitabine, and clofarabine), bilirubin, (ii) other chemotherapeutic agents such as benzoca alkaloids (e.g., etoposide, vinblastine, and vincristine), cisplatin, procarbazine, hydroxyurea, azacitidine, irinotecan, interferon alpha, interleukin-2, oxaliplatin, carboplatin, nedaplatin, and miriplatin; (ii) opioid analgesics (e.g., morphine); (iii) dopamine receptor D1D2 agonists (e.g., apomorphine), GIP; (iv) vomiting and / or nausea induced by chemotherapeutic agents such as cannabis and cannabinoid products (including cannabis hypersensitivity syndrome); (3) Vomiting or nausea caused by radiation damage or radiation therapy to the chest, abdomen, etc. used to treat cancer (4) Vomiting or nausea caused by a toxic substance or toxin; (5) Vomiting and nausea caused by pregnancy, including hyperemesis gravidarum; (6) Vomiting and nausea caused by vestibular disorders such as motion sickness and dizziness, (7) opioid withdrawal; (8) Pregnancy, including hyperemesis gravidarum (9) Vestibular disorders such as motion sickness and dizziness (10) Physical injury causing localized, generalized, acute, or chronic pain.

[0029] (18) The method according to any one of embodiments (16), wherein vomiting is treated in a subject not taking a medication for controlling a metabolic syndrome disorder.

[0030] (19) A GIP receptor agonist peptide according to any one of (1) to (8), which selectively activates the GIP receptor and exhibits anti-diabetic, anti-obesity, and anti-emetic effects in vivo.

[0031] It is to be understood that this disclosure is not limited to the particular methodology, protocols, and reagents, etc., described herein, as these may vary. The terminology used herein is for the purpose of describing particular embodiments only, and is not intended to limit the scope of the disclosure, which is defined solely by the claims. Other features and advantages of the present disclosure will be apparent from the following detailed description, drawings, and claims. [Brief explanation of the drawings]

[0032] [Figure 1A] Exemplary GIP receptor agonist peptides of the present disclosure are represented by any one of formulas (I)-(VIII). [Figure 1B] Exemplary GIP receptor agonist peptides of the present disclosure are represented by any one of formulas (I)-(VIII). [Figure 1C] Exemplary GIP receptor agonist peptides of the present disclosure are represented by any one of formulas (I)-(VIII). [Figure 1D] Exemplary GIP receptor agonist peptides of the present disclosure are represented by any one of formulas (I)-(VIII). [Figure 1E] Exemplary GIP receptor agonist peptides of the present disclosure are represented by any one of formulas (I)-(VIII). [Figure 1F]Exemplary GIP receptor agonist peptides of the present disclosure are represented by any one of formulas (I)-(VIII). DETAILED DESCRIPTION OF THE INVENTION

[0033] The definition of each substituent used herein is detailed below. Unless otherwise specified, each substituent has the following definition.

[0034] As used herein, examples of the "halogen atom" include fluorine, chlorine, bromine, and iodine.

[0035] In this specification, "C 1-6 Examples of "alkyl groups" 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.

[0036] As used herein, "optionally halogenated C 1-6 Examples of the "alkyl group" include C alkyl groups optionally containing 1 to 7, preferably 1 to 5, halogen atoms. 1-6 Specific examples thereof include alkyl groups, such as 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.

[0037] In this specification, "C 2-6Examples of "alkenyl groups" 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.

[0038] In this specification, "C 2-6 Examples of "alkynyl groups" include, but are not limited to, 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.

[0039] In this specification, "C 3-10 Examples of the "cycloalkyl group" include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, bicyclo[2.2.1]heptyl, bicyclo[2.2.2]octyl, bicyclo[3.2.1]octyl, and bicyclo[3.2.1]octyl. Examples include octyl and adamantyl.

[0040] As used herein, "optionally halogenated C 3-10 Examples of the "alkyl group" include C alkyl groups optionally containing 1 to 7, preferably 1 to 5, halogen atoms. 3-10 Specific examples of alkyl groups include cyclopropyl, 2,2-difluorocyclopropyl, 2,3-difluorocyclopropyl, cyclobutyl, difluorocyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl.

[0041] In this specification, "C 3-10 Examples of "cycloalkenyl groups" include cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, and cyclooctenyl.

[0042] In this specification, "C 6-14 Examples of "aryl groups" include phenyl, 1-naphthyl, 2-naphthyl, 1-anthryl, 2-anthryl, and 9-anthryl.

[0043] In this specification, "C 7-16 Examples of the "aralkyl group" include benzyl, phenethyl, naphthylmethyl, and phenylpropyl.

[0044] In this specification, "C 1-6 Examples of "alkoxy groups" include methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, tert-butoxy, pentyloxy, and hexyloxy.

[0045] As used herein, "optionally halogenated C 1-6 Examples of the "alkoxy group" include C alkyl groups optionally containing 1 to 7, preferably 1 to 5, halogen atoms. 1-6 Specific examples of alkoxy groups include methoxy, difluoromethoxy, trifluoromethoxy, ethoxy, 2,2,2-trifluoroethoxy, propoxy, isopropoxy, butoxy, 4,4,4-trifluorobutoxy, isobutoxy, sec-butoxy, pentyloxy, and hexyloxy.

[0046] In this specification, "C 3-10 Examples of the "cycloalkyloxy group" include cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy, cycloheptyloxy, and cyclooctyloxy.

[0047] In this specification, "C 1-6 Examples of the "alkylthio group" include methylthio, ethylthio, propylthio, isopropylthio, butylthio, sec-butylthio, tert-butylthio, pentylthio, and hexylthio.

[0048] As used herein, "optionally halogenated C1-6 Examples of the "alkylthio group" include C alkylthio groups optionally containing 1 to 7, preferably 1 to 5, halogen atoms. 1-6 Specific examples of alkylthio groups include methylthio, difluoromethylthio, trifluoromethylthio, ethylthio, propylthio, isopropylthio, butylthio, 4,4,4-trifluorobutylthio, pentylthio, and hexylthio.

[0049] In this specification, "C 1-6 Examples of "alkyl-carbonyl groups" include acetyl, propanoyl, butanoyl, 2-methylpropanoyl, pentanoyl, 3-methylbutanoyl, 2-methylbutanoyl, 2,2-dimethylpropanoyl, hexanoyl, and heptanoyl.

[0050] As used herein, "optionally halogenated C 1-6 Examples of the "alkyl-carbonyl group" include C alkyl-carbonyl groups optionally containing 1 to 7, preferably 1 to 5, halogen atoms. 1-6 Alkyl -carbonyl groups, specific examples of which include acetyl, chloroacetyl, trifluoroacetyl, trichloroacetyl, propanoyl, butanoyl, pentanoyl, and hexanoyl.

[0051] In this specification, "C 1-6 Examples of "alkoxy-carbonyl groups" include methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, isobutoxycarbonyl, sec-butoxycarbonyl, tert-butoxycarbonyl, pentyloxycarbonyl, and hexyloxycarbonyl.

[0052] In this specification, "C 6-14 Examples of the "aryl-carbonyl group" include benzoyl, 1-naphthoyl, and 2-naphthoyl.

[0053] In this specification, "C 7-16Examples of the "aralkyl-carbonyl group" include phenylacetyl and phenylpropionyl.

[0054] In the present specification, examples of the "5- to 14-membered aromatic heterocyclylcarbonyl group" include nicotinoyl, isonicotinoyl, thenoyl, and furoyl.

[0055] In the present specification, examples of the "3- to 14-membered non-aromatic heterocyclylcarbonyl group" include morpholinylcarbonyl, piperidinylcarbonyl, and pyrrolidinylcarbonyl.

[0056] As used herein, "mono- or di-C 1-6 Examples of the "alkyl-carbamoyl group" include methylcarbamoyl, ethylcarbamoyl, dimethylcarbamoyl, diethylcarbamoyl, and N-ethyl-N-methylcarbamoyl.

[0057] As used herein, "mono- or di-C 7-16 Examples of the "aralkyl-carbamoyl group" include benzylcarbamoyl and phenethylcarbamoyl.

[0058] In this specification, "C 1-6 Examples of the "alkylsulfonyl group" include methylsulfonyl, ethylsulfonyl, propylsulfonyl, isopropylsulfonyl, butylsulfonyl, sec-butylsulfonyl, and tert-butylsulfonyl.

[0059] As used herein, "optionally halogenated C 1-6 Examples of the "alkylsulfonyl group" include C alkylsulfonyl groups optionally containing 1 to 7, preferably 1 to 5, halogen atoms. 1-6Specific examples thereof include alkylsulfonyl groups, such as methylsulfonyl, difluoromethylsulfonyl, trifluoromethylsulfonyl, ethylsulfonyl, propylsulfonyl, isopropylsulfonyl, butylsulfonyl, 4,4,4-trifluorobutylsulfonyl, pentylsulfonyl, and hexylsulfonyl.

[0060] In this specification, "C 6-14 Examples of the "arylsulfonyl group" include phenylsulfonyl, 1-naphthylsulfonyl, and 2-naphthylsulfonyl.

[0061] As used herein, examples of "substituents" include halogen atoms, cyano groups, nitro groups, optionally substituted hydrocarbon groups, optionally substituted heterocyclic groups, acyl groups, optionally substituted amino groups, optionally substituted carbamoyl groups, optionally substituted thiocarbamoyl groups, optionally substituted sulfamoyl groups, optionally substituted hydroxy groups, optionally substituted sulfanyl (SH) groups, and optionally substituted silyl groups.

[0062] In the present specification, examples of the "hydrocarbon group" (including the "hydrocarbon group" of the "optionally substituted hydrocarbon group") include C 1-6 Alkyl group, C 2-6 Alkenyl group, C 2-6 Alkynyl group, C 3-10 Cycloalkyl groups, C 3-10 Cycloalkenyl group, C 6-14 Aryl groups, and C 7-16 Examples include aralkyl groups.

[0063] As used herein, examples of "optionally substituted hydrocarbon groups" include hydrocarbon groups optionally having a substituent(s) selected from the following Substituent A. "Substituent A" (1) a halogen atom, (2) a nitro group, (3) a cyano group, (4) an oxo group, (5) a hydroxy group, (6) optionally halogenated C 1-6 alkoxy groups, (7) C 6-14 aryloxy groups (e.g., phenoxy, naphthoxy); (8) C 7-16 aralkyloxy groups (e.g., benzyloxy), (9) 5- to 14-membered aromatic heterocyclyloxy groups (e.g., pyridyloxy), (10) 3- to 14-membered non-aromatic heterocyclyloxy groups (e.g., morpholinyloxy, piperidinyloxy), (11)C 1-6 alkyl-carbonyloxy groups (e.g., acetoxy, propanoyloxy); (12)C 6-14 arylcarbonyloxy groups (e.g., benzoyloxy, 1-naphthoyloxy, 2-naphthoyloxy); (13)C 1-6 alkoxy-carbonyloxy groups (e.g., methoxycarbonyloxy, ethoxycarbonyloxy, propoxycarbonyloxy, butoxycarbonyloxy); (14) Mono- or di-C 1-6 alkyl-carbamoyloxy groups (e.g., methylcarbamoyloxy, ethylcarbamoyloxy, dimethylcarbamoyloxy, diethylcarbamoyloxy); (15)C 6-14 aryl-carbamoyloxy groups (e.g., phenylcarbamoyloxy, naphthylcarbamoyloxy); (16) 5- to 14-membered aromatic heterocyclylcarbonyloxy groups (e.g., nicotinoyloxy), (17) 3- to 14-membered non-aromatic heterocyclylcarbonyloxy groups (e.g., morpholinylcarbonyloxy, piperidinylcarbonyloxy), (18) optionally halogenated C 1-6 alkylsulfonyloxy groups (e.g., methylsulfonyloxy, trifluoromethylsulfonyloxy); (19) Optional C 1-6C substituted by a group 6-14 arylsulfonyloxy groups (e.g., phenylsulfonyloxy, toluenesulfonyloxy); (20) optionally halogenated C 1-6 alkylthio groups, (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, (25) optionally halogenated C 1-6 alkyl-carbonyl groups, (26)C 6-14 aryl-carbonyl groups, (27) a 5- to 14-membered aromatic heterocyclylcarbonyl group, (28) a 3- to 14-membered non-aromatic heterocyclylcarbonyl group, (29)C 1-6 alkoxy-carbonyl groups, (30)C 6-14 aryloxy-carbonyl groups (e.g., phenyloxycarbonyl, 1-naphthyloxycarbonyl, 2-naphthyloxycarbonyl); (31)C 7-16 aralkyloxy-carbonyl groups (e.g., benzyloxycarbonyl, phenethyloxycarbonyl), (32) a carbamoyl group, (33) a thiocarbamoyl group, (34) Mono- or di-C 1-6 alkyl-carbamoyl groups, (35)C 6-14 aryl-carbamoyl groups (e.g., phenylcarbamoyl); (36) 5- to 14-membered aromatic heterocyclylcarbamoyl groups (e.g., pyridylcarbamoyl, thienylcarbamoyl), (37) 3- to 14-membered non-aromatic heterocyclylcarbamoyl groups (e.g., morpholinylcarbamoyl, piperidinylcarbamoyl), (38) optionally halogenated C 1-6 alkylsulfonyl groups, (39)C 6-14 arylsulfonyl groups, (40) 5- to 14-membered aromatic heterocyclylsulfonyl groups (e.g., pyridylsulfonyl, thienylsulfonyl), (41) Optionally halogenated C 1-6 alkylsulfinyl groups, (42)C 6-14 arylsulfinyl groups (e.g., phenylsulfinyl, 1-naphthylsulfinyl, 2-naphthylsulfinyl); (43) 5- to 14-membered aromatic heterocyclylsulfinyl groups (e.g., pyridylsulfinyl, thienylsulfinyl), (44) amino group, (45) Mono- or di-C 1-6 alkylamino groups (e.g., methylamino, ethylamino, propylamino, isopropylamino, butylamino, dimethylamino, diethylamino, dipropylamino, dibutylamino, N-ethyl-N-methylamino); (46) Mono- or di-C 6-14 arylamino groups (e.g., phenylamino); (47) 5- to 14-membered aromatic heterocyclylamino groups (e.g., pyridylamino), (48)C 7-16 aralkylamino groups (e.g., benzylamino), (49) formylamino group, (50)C 1-6 alkyl-carbonylamino groups (e.g., acetylamino, propanoylamino, butanoylamino); (51)(C 1-6 Alkyl)(C 1-6 alkyl-carbonyl)amino groups (e.g., N-acetyl-N-methylamino), (52)C 6-14 aryl-carbonylamino groups (e.g., phenylcarbonylamino, naphthylcarbonylamino); (53)C 1-6alkoxycarbonylamino groups (e.g., methoxycarbonylamino, ethoxycarbonylamino, propoxycarbonylamino, butoxycarbonylamino, tert-butoxycarbonylamino), (54)C 7-16 aralkyloxy-carbonylamino groups (e.g., benzyloxycarbonylamino), (55)C 1-6 alkylsulfonylamino groups (e.g., methylsulfonylamino, ethylsulfonylamino), (56) Optional C 1-6 C substituted by alkyl groups 6-14 arylsulfonylamino groups (e.g., phenylsulfonylamino, toluenesulfonylamino); (57) Optionally halogenated C 1-6 alkyl groups, (58)C 2-6 alkenyl groups, (59)C 2-6 alkynyl groups, (60)C 3-10 cycloalkyl groups, (61)C 3-10 cycloalkenyl groups, and (62)C 6-14 Aryl groups.

[0064] The number of the above-mentioned substituents in the "optionally substituted hydrocarbon group" is, for example, 1 to 5, preferably 1 to 3. When the number of substituents is 2 or more, the respective substituents may be the same or different.

[0065] In this specification, examples of the "heterocyclic group" (including the "heterocyclic group" of "optionally substituted heterocyclic group") include (i) aromatic heterocyclic groups, (ii) non-aromatic heterocyclic groups, and (iii) 7- to 10-membered bridged heterocyclic groups, each of which contains, as ring-constituting atoms other than carbon, 1 to 4 heteroatoms selected from nitrogen atoms, sulfur atoms, and oxygen atoms.

[0066] In this specification, examples of the "aromatic heterocyclic group" (including "5- to 14-membered aromatic heterocyclic group") include 5- to 14-membered (preferably 5- to 10-membered) aromatic heterocyclic groups containing, as ring-constituting atoms other than carbon, 1 to 4 heteroatoms selected from nitrogen atoms, sulfur atoms, and oxygen atoms.

[0067] Preferred 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, and triazinyl, as well as benzothiophenyl, benzofuranyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzothiazolyl, benzisothiazolyl, benzotriazolyl, imidazopyridinyl, thienopyridinyl, furopyridinyl, pyrrolopyridinyl, and pyrazolo Examples thereof include 8- to 14-membered fused polycyclic (preferably bi- or tricyclic) aromatic heterocyclic groups such as pyridinyl, oxazolopyridinyl, thiazolopyridinyl, imidazopyrazinyl, imidazopyrimidinyl, 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, and phenoxazinyl.

[0068] In the present specification, examples of the "non-aromatic heterocyclic group" (including "3- to 14-membered non-aromatic heterocyclic group") include 3- to 14-membered (preferably 4- to 10-membered) non-aromatic heterocyclic groups containing, as ring-constituting atoms other than carbon, 1 to 4 heteroatoms selected from nitrogen atoms, sulfur atoms, and oxygen atoms.

[0069] Preferred examples of the "non-aromatic heterocyclic group" include aziridinyl, oxiranyl, thiiranyl, azetidinyl, oxetanyl, thietanyl, tetrahydrothienyl, tetrahydrofuranyl, pyrrolinyl, pyrrolidinyl, imidazolinyl, imidazolidinyl, oxazolinyl, oxazolidinyl, pyrazolinyl, pyrazolidinyl, thiazolinyl, thiazolidinyl, tetrahydroisothiazolyl, tetrahydrooxazolyl, tetrahydroisoxazolyl, piperidinyl, piperazinyl, tetrahydropyridinyl, and dihydropyridinyl. , dihydrothiopyranyl, tetrahydropyrimidinyl, tetrahydropyridazinyl, dihydropyranyl, tetrahydropyranyl, tetrahydrothiopyranyl, morpholinyl, thiomorpholinyl, azepanyl, diazepanyl, azepinyl, oxepanyl, azocanyl, diazocanyl, and the like; and dihydrobenzofuranyl, dihydrobenzimidazolyl, dihydrobenzoxazolyl, dihydrobenzothiazolyl, dihydrobenzisothiazolyl, dihydronaphtho[2,3-b]thienyl, tetrahydroisothiazolyl ... Examples of the heterocyclic group include 9- to 14-membered fused polycyclic (preferably bicyclic or tricyclic) non-aromatic heterocyclic groups such as hexahydroquinolyl, tetrahydroquinolyl, 4H-quinolidinyl, indolinyl, isoindolinyl, tetrahydrothieno[2,3-c]pyridinyl, tetrahydrobenzazepinyl, tetrahydroquinoxalinyl, tetrahydrophenanthridinyl, hexahydrophenothiazinyl, hexahydrophenoxazinyl, tetrahydrophthalazinyl, tetrahydronathyridinyl, tetrahydroquinazolinyl, tetrahydrocinnolinyl, tetrahydrocarbazolyl, tetrahydro-β-carbolinyl, tetrahydroacridinyl, tetrahydrophenazinyl, tetrahydrothioxanthenyl, and octahydroisoquinylyl.

[0070] In the present specification, preferred examples of the "7- to 10-membered bridged heterocyclic group" include quinuclidinyl and 7-azabicyclo[2.2.1]heptanyl.

[0071] In the present specification, examples of the "nitrogen-containing heterocyclic group" include a "heterocyclic group" containing at least one nitrogen atom as a ring-constituting atom.

[0072] In this specification, examples of the "optionally substituted heterocyclic group" include heterocyclic groups optionally having substituent(s) selected from the above-mentioned Substituent Group A.

[0073] The number of substituents in the "optionally substituted heterocyclic group" is, for example, 1 to 3. When the number of substituents is two or more, the respective substituents may be the same or different.

[0074] As used herein, examples of "acyl groups" include formyl groups, carboxy groups, carbamoyl groups, thiocarbamoyl groups, sulfino groups, sulfo groups, sulfamoyl groups, and phosphono groups, each of which is optionally "substituted with a halogen atom, an optionally halogenated C 1-6 C having 1 to 3 substituents selected from an alkoxy group, a hydroxy group, a nitro group, a cyano group, an amino group, and a carbamoyl group 1-6 Alkyl group, C 2-6 Alkenyl group, C 3-10 Cycloalkyl groups, C 3-10 Cycloalkenyl group, C 6-14 Aryl group, C 7-16 and optionally having one or two substituents selected from an aralkyl group, a 5- to 14-membered aromatic heterocyclic group, and a 3- to 14-membered non-aromatic heterocyclic group.

[0075] Examples of "acyl groups" (also referred to as "Ac") also include hydrocarbyl-sulfonyl groups, heterocyclylsulfonyl groups, hydrocarbyl-sulfinyl groups, and heterocyclylsulfinyl groups.

[0076] In some embodiments, a hydrocarbon-sulfonyl group refers to a sulfonyl group having a hydrocarbon group attached thereto, a heterocyclylsulfonyl group refers to a sulfonyl group having a heterocyclic group attached thereto, a hydrocarbon-sulfinyl group refers to a sulfinyl group having a hydrocarbon group attached thereto, and a heterocyclylsulfinyl group refers to a sulfinyl group having a heterocyclic group attached thereto.

[0077] Preferred examples of the "acyl group" include a formyl group, a carboxy group, and C 1-6 Alkyl-carbonyl group, C 2-6 Alkenyl-carbonyl groups (e.g., crotonoyl), C 3-10 Cycloalkyl-carbonyl groups (e.g., cyclobutanecarbonyl, cyclopentanecarbonyl, cyclohexanecarbonyl, cycloheptanecarbonyl), C 3-10 Cycloalkenyl-carbonyl groups (e.g., 2-cyclohexenecarbonyl), C 6-14 Aryl-carbonyl group, C 7-16 Aralkyl-carbonyl group, 5- to 14-membered aromatic heterocyclylcarbonyl group, 3- to 14-membered non-aromatic heterocyclylcarbonyl group, C 1-6 Alkoxy-carbonyl group, C 6-14 Aryloxy-carbonyl groups (e.g., phenyloxycarbonyl, naphthyloxycarbonyl), C 7-16 Aralkyloxy-carbonyl groups (e.g., benzyloxycarbonyl, phenethyloxycarbonyl), carbamo yl group, mono- or di-C 1-6 Alkyl-carbamoyl group, mono- or di-C 2-6 Alkenyl-carbamoyl groups (e.g., diallylcarbamoyl), mono- or di-C 3-10 Cycloalkyl-carbamoyl groups (e.g., cyclopropylcarbamoyl), mono- or di-C 6-14 Aryl-carbamoyl groups (e.g., phenylcarbamoyl), mono- or di-C 7-16 Aralkyl-carbamoyl group, 5- to 14-membered aromatic heterocyclylcarbamoyl group (e.g., pyridylcarbamoyl), thiocarbamoyl group, mono- or di-C 1-6Alkyl-thiocarbamoyl groups (e.g., methylthiocarbamoyl, N-ethyl-N-methylthiocarbamoyl), mono- or di-C 2-6 Alkenyl-thiocarbamoyl groups (e.g., diallylthiocarbamoyl), mono- or di-C 3-10 Cycloalkyl-thiocarbamoyl groups (e.g., cyclopropylthiocarbamoyl, cyclohexylthiocarbamoyl), mono- or di-C 6-14 Aryl-thiocarbamoyl groups (e.g., phenylthiocarbamoyl), mono- or di-C 7-16 Aralkyl-thiocarbamoyl groups (e.g., benzylthiocarbamoyl, phenethylthiocarbamoyl), 5- to 14-membered aromatic heterocyclylthiocarbamoyl groups (e.g., pyridylthiocarbamoyl), sulfino groups, C 1-6 Alkyl sulfinyl group (e.g., methyl sulfinyl, ethyl sulfinyl), sulfo group, C 1-6 Alkylsulfonyl group, C 6-14 Arylsulfonyl group, phosphono group, mono- or di-C 1-6 Examples include alkylphosphono groups (for example, dimethylphosphono, diethylphosphono, diisopropylphosphono, dibutylphosphono).

[0078] In the present specification, examples of the "optionally substituted amino group" include "C 1-6 Alkyl group, C 2-6 Alkenyl group, C 3-10 Cycloalkyl groups, C 6-14 Aryl group, C 7-16 Aralkyl group, C 1-6 Alkyl-carbonyl group, C 6-14 Aryl-carbonyl group, C 7-16 Aralkyl-carbonyl group, 5- to 14-membered aromatic heterocyclylcarbonyl group, 3- to 14-membered non-aromatic heterocyclylcarbonyl group, C 1-6 Alkoxy-carbonyl group, 5- to 14-membered aromatic heterocyclic group, carbamoyl group, mono- or di-C 1-6 Alkyl-carbamoyl group, mono- or di-C 7-16Aralkyl-carbamoyl group, C 1-6 Alkylsulfonyl group, and C 6-14 and arylsulfonyl groups.

[0079] Preferred examples of optionally substituted amino groups include amino groups, mono- or di-(optionally substituted C 1-6 alkyl)amino groups (e.g., methylamino, trifluoromethylamino, dimethylamino, ethylamino, diethylamino, propylamino, dibutylamino), mono- or di-C 2-6 Alkenylamino groups (e.g., diallylamino), mono- or di-C 3-10 Cycloalkylamino groups (e.g., cyclopropylamino, cyclohexylamino), mono- or di-C 6-14 Arylamino groups (e.g., phenylamino), mono- or di-C 7-16 Aralkylamino groups (e.g., benzylamino, dibenzylamino), mono- or di-(optionally halogenated C 1-6 alkyl)-carbonylamino group (e.g., acetylamino, propionylamino), mono- or di-C 6-14 Aryl-carbonylamino groups (e.g., benzoylamino), mono- or di-C 7-16 Aralkyl-carbonylamino group (e.g., benzylcarbonylamino), mono- or di-5- to 14-membered aromatic heterocyclic carbonylamino group (e.g., nicotinoylamino, isonicotinoylamino), mono- or di-3- to 14-membered non-aromatic heterocyclic carbonylamino group (e.g., piperidinylcarbonylamino), mono- or di-C 1-6 Alkoxy-carbonylamino group (e.g., tert-butoxycarbonylamino), 5- to 14-membered aromatic heterocyclic amino group (e.g., pyridylamino), carbamoylamino group, (mono- or di-C 1-6 alkyl-carbamoyl)amino groups (e.g., methylcarbamoylamino), (mono- or di-C 7-16 aralkyl-carbamoyl)amino group (e.g., benzylcarbamoylamino), C1-6 Alkyl sulfonyl amine groups (e.g., methylsulfonylamino, ethylsulfonylamino), C 6-14 Arylsulfonylamino groups (e.g., phenylsulfonylamino), (C 1-6 Alkyl)(C 1-6 alkyl-carbonyl)amino groups (e.g., N-acetyl-N-methylamino), and (C 1-6 Alkyl)(C 6-14 and aryl-carbonyl)amino groups (for example, N-benzoyl-N-methylamino).

[0080] In this specification, examples of the "optionally substituted carbamoyl group" include "C 1-6 Alkyl group, C 2-6 Alkenyl group, C 3-10 Cycloalkyl groups, C 6-14 Aryl group, C 7-16 Aralkyl group, C 1-6 Alkyl-carbonyl group, C 6-14 Aryl-carbonyl group, C 7-16 Aralkyl-carbonyl group, 5- to 14-membered aromatic heterocyclylcarbonyl group, 3- to 14-membered non-aromatic heterocyclylcarbonyl group, C 1-6 Alkoxy-carbonyl group, 5- to 14-membered aromatic heterocyclic group, carbamoyl group, mono- or di-C 1-6 Alkyl-carbamoyl group, and mono- or di-C 7-16 and carbamoyl groups optionally having one or two substituents selected from aralkyl-carbamoyl groups.

[0081] Preferred examples of optionally substituted carbamoyl groups include carbamoyl groups, mono- or di-C 1-6 Alkyl-carbamoyl group, mono- or di-C 2-6 Alkenyl-carbamoyl groups (e.g., diallylcarbamoyl), mono- or di-C 3-10Cycloalkyl-carbamoyl groups (e.g., cyclopropylcarbamoyl, cyclohexylcarbamoyl), mono- or di-C 6-14 Aryl-carbamoyl groups (e.g., phenylcarbamoyl), mono- or di-C 7-16 Aralkyl-carbamoyl group, mono- or di-C 1-6 Alkyl-carbamoyl-carbamoyl groups (e.g., acetylcarbamoyl, propionylcarbamoyl), mono- or di-C 6-14 Examples include aryl-carbonyl-carbamoyl groups (for example, benzoylcarbamoyl) and 5- to 14-membered aromatic heterocyclylcarbamoyl groups (for example, pyridylcarbamoyl).

[0082] In this specification, examples of the "optionally substituted thiocarbamoyl group" include "C thiocarbamoyl groups each having 1 to 3 substituents optionally selected from Substituent group A". 1-6 Alkyl group, C 2-6 Alkenyl group, C 3-10 Cycloalkyl groups, C 6-14 Aryl group, C 7-16 Aralkyl group, C 1-6 Alkyl-carbonyl group, C 6-14 Aryl-carbonyl group, C 7-16 Aralkyl-carbonyl group, 5- to 14-membered aromatic heterocyclylcarbonyl group, 3- to 14-membered non-aromatic heterocyclylcarbonyl group, C 1-6 Alkoxy-carbonyl group, 5- to 14-membered aromatic heterocyclic group, carbamoyl group, mono- or di-C 1-6 Alkyl-carbamoyl group, and mono- or di-C 7-16 and thiocarbamoyl groups optionally having one or two substituents selected from aralkyl-carbamoyl groups.

[0083] Preferred examples of the optionally substituted thiocarbamoyl group include thiocarbamoyl groups, mono- or di-C 1-6Alkyl-thiocarbamoyl groups (e.g., methylthiocarbamoyl, ethylthiocarbamoyl, dimethylthiocarbamoyl, diethylthiocarbamoyl, N-ethyl-N-methylthiocarbamoyl), mono- or di-C 2-6 Alkenyl-thiocarbamoyl groups (e.g., diallylthiocarbamoyl), mono- or di-C 3-10 Cycloalkyl-thiocarbamoyl groups (e.g., cyclopropylthiocarbamoyl, cyclohexylthiocarbamoyl), mono- or di-C 6-14 Aryl-thiocarbamoyl groups (e.g., phenylthiocarbamoyl), mono- or di-C 7-16 Aralkyl-thiocarbamoyl groups (e.g., benzylthiocarbamoyl, phenylthiocarbamoyl), mono- or di-C 1-6 Alkyl-carbonyl-thiocarbamoyl groups (e.g., acetylthiocarbamoyl, propionylthiocarbamoyl), mono- or di-C 6-14 Aryl-carbonyl-thiocarbamoyl groups (e.g., benzoylthiocarbamoyl ), and 5- to 14-membered aromatic heterocyclylthiocarbamoyl groups (for example, pyridylthiocarbamoyl).

[0084] In the present specification, examples of the "optionally substituted sulfamoyl group" include "C 1-6 Alkyl group, C 2-6 Alkenyl group, C 3-10 Cycloalkyl groups, C 6-14 Aryl group, C 7-16 Aralkyl group, C 1-6 Alkyl-carbonyl group, C 6-14 Aryl-carbonyl group, C 7-16 Aralkyl-carbonyl group, 5- to 14-membered aromatic heterocyclylcarbonyl group, 3- to 14-membered non-aromatic heterocyclylcarbonyl group, C 1-6 Alkoxy-carbonyl group, 5- to 14-membered aromatic heterocyclic group, carbamoyl group, mono- or di-C 1-6 Alkyl-carbamoyl group, and mono- or di-C 7-16and sulfamoyl groups optionally having one or two substituents selected from aralkyl-carbamoyl groups.

[0085] Preferred examples of optionally substituted sulfamoyl groups include sulfamoyl groups, mono- or di-C 1-6 Alkyl-sulfamoyl groups (e.g., methylsulfamoyl, ethylsulfamoyl, dimethylsulfamoyl, diethylsulfamoyl, N-ethyl-N-methylsulfamoyl), mono- or di-C 2-6 Alkenyl-sulfamoyl groups (e.g., diallylsulfamoyl), mono- or di-C 3-10 Cycloalkyl-sulfamoyl groups (e.g., cyclopropylsulfamoyl, cyclohexylsulfamoyl), mono- or di-C 6-14 Aryl-sulfamoyl groups (e.g., phenylsulfamoyl), mono- or di-C 7-16 Aralkyl-sulfamoyl group (e.g., benzylsulfamoyl, phenethylsulfamoyl), mono- or di-C 1-6 Alkyl-carbonyl-sulfamoyl group (e.g., acetylsulfamoyl, propionylsulfamoyl), mono- or di-C 6-14 Examples thereof include aryl-carbonyl-sulfamoyl groups (for example, benzoylsulfamoyl) and 5- to 14-membered aromatic heterocyclylsulfamoyl groups (for example, pyridylsulfamoyl).

[0086] In the present specification, examples of the "optionally substituted hydroxy group" include "C 1-6 Alkyl group, C 2-6 Alkenyl group, C 3-10 Cycloalkyl groups, C 6-14 Aryl group, C 7-16 Aralkyl group, C 1-6 Alkyl-carbonyl group, C 6-14 Aryl-carbonyl group, C 7-16Aralkyl-carbonyl group, 5- to 14-membered aromatic heterocyclylcarbonyl group, 3- to 14-membered non-aromatic heterocyclylcarbonyl group, C 1-6 Alkoxy-carbonyl group, 5- to 14-membered aromatic heterocyclic group, carbamoyl group, mono- or di-C 1-6 Alkyl-carbamoyl group, mono- or di-C 7-16 Aralkyl-carbamoyl group, C 1-6 Alkylsulfonyl group, and C 6-14 arylsulfonyl groups.

[0087] Preferred examples of the optionally substituted hydroxy group include a hydroxy group, C 1-6 Alkoxy group, C 2-6 Alkenyloxy groups (e.g., allyloxy, 2-butenyloxy, 2-pentenyloxy, 3-hexenyloxy), C 3-10 cycloalkyloxy groups (e.g., cyclohexyloxy), C 6-14 Aryloxy groups (e.g., phenoxy, naphthyloxy), C 7-16 Aralkyloxy groups (e.g., benzyloxy, phenethyloxy), C 1-6 Alkyl-carbonyloxy groups (e.g., acetyloxy, propionyloxy, butyryloxy, isobutyryloxy, pivaloyloxy), C 6-14 Aryl-carbonyloxy groups (e.g., benzoyloxy), C 7-16 Aralkyl-carbonyloxy groups (e.g., benzylcarbonyloxy), 5- to 14-membered aromatic heterocyclylcarbonyloxy groups (e.g., nicotinoyloxynicotinoyloxy), 3- to 14-membered non-aromatic heterocyclylcarbonyloxy groups (e.g., piperidinylcarbonyloxy), C 1-6 Alkoxy-carbonyloxy groups (e.g., tert-butoxycarbonyloxy groups) nyloxy), 5- to 14-membered aromatic heterocyclyloxy groups (e.g., pyridyloxy), carbamoyloxy groups, C 1-6 Alkyl-carbamoyloxy groups (e.g., methylcarbamoyloxy), C 7-16Aralkyl-carbamoyloxy groups (e.g., benzylcarbamoyloxy), C 1-6 Alkyl sulfonyloxy groups (e.g., methyl sulfonyloxy, ethyl sulfonyloxy), and C 6-14 Arylsulfonyloxy groups (for example, phenylsulfonyloxy) are included.

[0088] In this specification, examples of the "optionally substituted sulfanyl group" include "C 1-6 Alkyl group, C 2-6 Alkenyl group, C 3-10 Cycloalkyl groups, C 6-14 Aryl group, C 7-16 Aralkyl group, C 1-6 Alkyl-carbonyl group, C 6-14 Examples thereof include a sulfanyl group and a halogenated sulfanyl group optionally having a substituent selected from an aryl-carbonyl group and a 5- to 14-membered aromatic heterocyclic group.

[0089] Preferred examples of the optionally substituted sulfanyl group include a sulfanyl (—SH) group, C 1-6 Alkylthio group, C 2-6 Alkenylthio groups (e.g., allylthio, 2-butenylthio, 2-pentenylthio, 3-hexenylthio), C 3-10 cycloalkylthio groups (e.g., cyclohexylthio), C 6-14 Alkylthio groups (e.g., phenylthio, naphthylthio), C 7-16 Aralkylthio groups (e.g., benzylthio, phenethylthio), C 1-6 Alkylcarbonylthio groups (e.g., acetylthio, propionylthio, butyrylthio, isobutyrylthio, pivaloylthio), C 6-14 Examples include aryl-carbonylthio groups (eg, benzoylthio), 5- to 14-membered aromatic heterocyclylthio groups (eg, pyridylthio), and halogenated thio groups (eg, pentafluorothio).

[0090] In the present specification, examples of the "optionally substituted silyl group" include "C silyl groups each optionally having 1 to 3 substituents selected from Substituent Group A". 1-6 Alkyl group, C 2-6 Alkenyl group, C 3-10 Cycloalkyl groups, C 6-14 Aryl groups, and C 7-16 and silyl groups optionally having 1 to 3 substituents selected from aralkyl groups.

[0091] Examples of optionally substituted silyl groups include tri-C 1-6 Examples include alkylsilyl groups (for example, trimethylsilyl, tert-butyl(dimethyl)silyl).

[0092] For the description of amino acid residues, the following rules may be illustrative: 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.

[0093] Also, for convenience, and as will be readily known to those of skill in the art, the following abbreviations or symbols are used to represent moieties, reagents, etc. used in this disclosure:

[0094] Mono-haloPhe: mono-halophenylalanine.

[0095] Bis-haloPhe: bis-halophenylalanine.

[0096] Mono-haloTyr: Mono-halotyrosine.

[0097] Bis-haloTyr: Bis-halotyrosine.

[0098] (D)-Tyr: D-tyrosine.

[0099] (D)-Ala: D-alanine.

[0100] DesNH2-Tyr: desaminotyrosine.

[0101] (D)-Phe-D: phenylalanine.

[0102] DesNH2-Phe: desaminophenylalanine.

[0103] (D)-Trp: D-tryptophan.

[0104] (D) 3Pya: D-3-pyridylalanine.

[0105] 2-Cl-(D)Phe: D-2-chlorophenylalanine.

[0106] 3-Cl-(D)Phe: D-3-chlorophenylalanine.

[0107] 4-Cl-(D)Phe: D-4-chlorophenylalanine.

[0108] 2-F-(D)Phe: D-2-fluorophenylalanine.

[0109] 3-F(D)Phe: D-3-fluorophenylalanine.

[0110] 3,5-diF-(D)Phe: D-3,5-difluorophenylalanine.

[0111] 3,4,5-triF-(D)Phe: D-3,4,5-trifluorophenylalanine.

[0112] D-Iva: D-Isovaline

[0113] SSA: succinimidoyl succinamide.

[0114] PEG: polyethylene glycol.

[0115] PEG m :(Methoxy)polyethylene glycol.

[0116] PEG m (12,000): (Methoxy) polyethylene glycol with a molecular weight of approximately 12 kD.

[0117] PEG m (20,000): (Methoxy) polyethylene glycol with a molecular weight of approximately 20 kD.

[0118] PEG m (30,000): (Methoxy) polyethylene glycol with a molecular weight of approximately 30 kD.

[0119] Fmoc: 9-fluorenylmethyloxycarbonyl.

[0120] DMF: dimethylformamide.

[0121] DIPEA: N,N-diisopropylethylamine.

[0122] TFA: Trifluoroacetic acid

[0123] HOBT: N-hydroxybenzotriazole.

[0124] BOP: Benzotriazol-1-yloxy-tris-(dimethylamino)phosphonium-hexafluorophosphate.

[0125] HBTU: 2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium-hexafluorophosphate.

[0126] NMP: N-methyl-pyrrolidone

[0127] FAB-MS: Fast atom bombardment mass spectrometry.

[0128] ES-MS: electrospray mass spectrometry.

[0129] Abu: α-aminobutyric acid.

[0130] Acc: 1-amino-1-cyclo(C3-C9) alkyl carboxylic acid.

[0131] A3c: 1-amino-1-cyclopropanecarboxylic acid.

[0132] A4c: 1-amino-1-cyclobutanecarboxylic acid.

[0133] A5c: 1-amino-1-cyclopentanecarboxylic acid.

[0134] A6c: 1-amino-1-cyclohexanecarboxylic acid.

[0135] Act: 4-amino-4-carboxytetrahydropyran.

[0136] Ado: 12-aminododecanoic acid.

[0137] Aib: α-aminoisobutyric acid.

[0138] Aic: 2-aminoindan-2-carboxylic acid.

[0139] β-Ala: beta-alanine.

[0140] Amp: 4-amino-phenylalanine.

[0141] Apc: 4-amino-4-carboxypiperidine.

[0142] hArg: homoarginine.

[0143] Aun: 11-aminoundecanoic acid.

[0144] Ava: 5-aminovaleric acid.

[0145] Cha: β-cyclohexylalanine.

[0146] Dhp: 3,4-dehydroproline.

[0147] Dmt: 5,5-dimethylthiazolidine-4-carboxylic acid.

[0148] GABA: gamma-aminobutyric acid.

[0149] 4Hppa: 3-(4-hydroxyphenyl)propionic acid.

[0150] Hyp: Hydroxyproline

[0151] 3Hyp: 3-hydroxyproline

[0152] 4Hyp: 4-hydroxyproline.

[0153] hPro: homoproline.

[0154] 4Ktp: 4-ketoproline.

[0155] Nle: norleucine.

[0156] NMe-Tyr: N-methyl-tyrosine.

[0157] 1Nal or 1-Nal: β-(1-naphthyl)alanine.

[0158] 2Nal or 2-Nal: β-(2-naphthyl)alanine.

[0159] Nva: Norvaline.

[0160] Orn: Ornithine.

[0161] 2Pal or 2-Pal: β-(2-pyridinyl)alanine.

[0162] 3Pal or 3-Pal: β-(3-pyridinyl)alanine.

[0163] 4Pal or 4-Pal: β-(4-pyridinyl)alanine.

[0164] Pen: Penicillamine

[0165] (3,4,5F)Phe: 3,4,5-trifluorophenylalanine.

[0166] (2,3,4,5,6)Phe: 2,3,4,5,6-pentafluorophenylalanine.

[0167] Psu: N-propylsuccinimide.

[0168] Iva: Isovaline.

[0169] Sar: Sarcosine.

[0170] Taz: β-(4-thiazolyl)alanine.

[0171] 3Thi: β-(3-thienyl)alanine.

[0172] Thz: thioproline.

[0173] Tic: tetrahydroisoquinoline-3-carboxylic acid.

[0174] Tle: tert-leucine.

[0175] Act: Acetonitrile.

[0176] Boc: tert-butyloxycarbonyl.

[0177] BSA: bovine serum albumin.

[0178] DCM: dichloromethane.

[0179] DTT: dithiothreitol.

[0180] ESI: electrospray ionization.

[0181] Fmoc: 9-fluorenylmethyloxycarbonyl.

[0182] HBTU: 2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium-hexafluorophosphate.

[0183] HPLC: High-performance liquid chromatography

[0184] IBMX: isobutylmethylxanthine;

[0185] LC-MS: liquid chromatography mass spectrometry.

[0186] Mtt: methyltrityl.

[0187] NMP: N-methylpyrrolidone.

[0188] 5K PEG: polyethylene glycol, which may include other functional groups or moieties such as linkers, and which is linear or branched as defined below, and has a weight average molecular weight of about 5,000 daltons.

[0189] 10K PEG: polyethylene glycol, which may include other functional groups or moieties such as linkers, and which is linear or branched as defined below, and has a weight average molecular weight of about 10,000 daltons.

[0190] 20K PEG: Polyethylene glycol, which may contain other functional groups or moieties such as linkers, and which is linear or branched as defined below, and has a molecular weight of about 20,000 daltons. The weight average molecular weight of

[0191] 30K PEG: polyethylene glycol, which may include other functional groups or moieties such as linkers, and which is linear or branched as defined below, and has a weight average molecular weight of about 30,000 daltons.

[0192] 40K PEG: polyethylene glycol, which may contain other functional groups or moieties such as linkers, and which is linear or branched as defined below, and has a weight average molecular weight of about 40,000 daltons.

[0193] 50K PEG: polyethylene glycol, which may include other functional groups or moieties such as linkers, and which is linear or branched as defined below, and has a weight average molecular weight of about 50,000 daltons.

[0194] 60K PEG: polyethylene glycol, which may include other functional groups or moieties such as linkers, and which is linear or branched as defined below, and has a weight average molecular weight of about 60,000 daltons.

[0195] PEG is available in a variety of molecular weights, based on the number of repeating ethylene oxide subunits (i.e., -OCH2CH2-) in the molecule. The mPEG formula is typically followed by a number corresponding to the average molecular weight. For example, PEG-200 has a weight-average molecular weight of 200 daltons and can have a molecular weight range of 190 to 210 daltons. Molecular weight in the context of water-soluble polymers such as PEG can be expressed as either number-average or weight-average molecular weight. Unless otherwise specified, all references to the molecular weight of mPEG herein refer to the weight-average molecular weight. Both number-average and weight-average molecular weight determinations can be measured using gel permeation chromatography or other liquid chromatography techniques. Other methods for determining molecular weight values ​​can also be used, such as the use of end-group analysis to determine number-average molecular weight or measurements of colligative properties (e.g., freezing point depression, boiling point elevation, or osmolality), or the use of light scattering techniques, ultracentrifugation, or viscometry to determine weight-average molecular weight.

[0196] tBU: tert-butyl.

[0197] TIS: triisopropylsilane.

[0198] Trt: trityl.

[0199] Z: benzyloxycarbonyl.

[0200] As used herein, a "PEG moiety" refers to polyethylene glycol (PEG) or a derivative thereof, such as (methoxy)polyethylene glycol (PEG m ) refers to

[0201] As used herein, a "PEGylated peptide" refers to a peptide in which at least one amino acid residue, e.g., Lys or Cys, is conjugated to a PEG moiety. "Conjugated" means that the PEG moiety is directly linked to the residue or linked to the residue via a spacer moiety, e.g., a crosslinker. When the conjugation is to a lysine residue, the lysine residue is referred to herein as a "PEGylated Lys." A peptide conjugated to only one MPEG moiety is referred to as a "monoPEGylated."

[0202] As used herein, "Lys-PEG" and "Lys-PEG m " are "Lys(epsilon-SSA-PEGn)" refers to a lysine residue whose epsilon-amino group has been crosslinked to MPEG using an appropriately functionalized SSA.

[0203] As used herein, the term "human native GIP peptide" refers to a naturally occurring human GIP peptide. This human native GIP peptide (42 amino acids) has the amino acid sequence YAEGTFISDYSIAMDKIHQ QDFVNWLLAQKGKKNDWKHNITQ (SEQ ID NO: 1) and is a functionally active molecule derived from the parent precursor set forth in the National Center for Biotechnology Information (NCBI) Reference Sequence: NP_004114.1; REFSEQ: Accession NM_004123.2 (SEQ ID NO: 2). This full-length precursor is encoded by the mRNA sequence of human gastric inhibitory polypeptide (GIP) mRNA, Accession: NM_004123; Version: NM_004123.2 (SEQ ID NO: 3).

[0204] "Percent (%) amino acid sequence identity" with respect to a reference polypeptide is defined as the percentage of amino acid residues in a candidate polypeptide sequence that are identical to those in the reference polypeptide sequence after aligning the sequences and introducing gaps, if necessary, to achieve the maximum percent sequence identity, and does not consider any conservative substitutions as part of the sequence identity. Alignment for purposes of determining percent amino acid sequence identity can be accomplished in a variety of ways within the skill of the art, for example, 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 maximum alignment over the full length of the sequences being compared.

[0205] As used herein, the term "treatment" (and variations thereof, such as "treat" or "treating") refers to a clinical intervention aimed at altering the natural course of a disease in an individual being treated, and may be performed for prophylaxis or during the course of clinical pathology. Desirable effects of treatment include, but are not limited to, preventing the occurrence or recurrence of a condition, alleviating symptoms, reducing the direct or indirect pathological consequences of a condition or treatment, preventing emesis, i.e., preventing the occurrence or slowing the rate of progression of symptoms associated in whole or in part with a condition or side effect known to accompany a particular treatment, improving or alleviating symptoms associated with emesis, such as nausea and / or vomiting, and achieving remission or improved prognosis. In some embodiments, the GIP receptor agonist peptides of the present disclosure are used to inhibit or delay the occurrence of emesis, i.e., to delay the progression of nausea or vomiting, or symptoms associated with emesis or vomiting, or to prevent, delay, or inhibit the onset of emesis, nausea, and / or vomiting associated with the treatment of a different disease being actively treated.

[0206] "Reduce" or "inhibit" refers to the ability to produce an overall decrease of 20%, 30%, 40%, 50%, 60%, 70%, 75%, 80%, 85%, 90%, 95%, or more. In some embodiments, reduction or inhibition can refer to a relative decrease compared to a reference (e.g., a reference level of biological activity (e.g., the number of nausea and / or vomiting episodes following administration to a subject of a prescribed amount of chemotherapy, e.g., a prescribed dose of a chemotherapeutic agent known to cause emesis)). In some embodiments, reduction or inhibition can refer to a relative reduction in side effects (i.e., nausea and / or vomiting) associated with treating a condition or disease.

[0207] Optimal alignment of sequences for comparison can be achieved, for example, by the local homology algorithm of Smith and Waterman (Adv. Appl. Math. 2:482 (1981)), which is incorporated herein by reference. This can be performed by the homology alignment algorithm of Unsch (J. Mol. Biol. 48:443-53 (1970), incorporated herein by reference), by the similarity search method of Pearson and Lipman (Proc. Natl. Acad. Sci. USA 85:2444-48 (1988), incorporated herein by reference), by computer 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)).

[0208] An example of an algorithm suitable for determining percent sequence identity and sequence similarity is the algorithm described by Altschul et al. (J. MoI. Biol. 215:403-410 (1990)). (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 herein by reference.) Software for performing BLAST analysis is publicly available from the internet website of the National Center for Biotechnology Information. This algorithm identifies high-scoring sequence pairs (HSPs) by first identifying short words W in length. A query sequence is obtained that matches or meets a positive threshold score T when aligned with words of the same length in database sequences. 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 possible to increase the cumulative alignment score. Extension of the word hits in each direction is stopped when the cumulative alignment score drops by a quantity X from its maximum achieved value, when the accumulation of one or more negative-scoring residue alignments causes the cumulative score to fall below zero, or when 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 herein by reference), alignments (B) of 50, expectation (E) of 10, M=5, N=-4, and a comparison of both strands.

[0209] In addition to calculating the percent sequence identity, the BLAST algorithm also performs a statistical analysis of the similarity between two sequences (see, for example, Karlin and Altschul, Proc. Natl. Acad. Sci. USA 90:5873-77 (1993), which is incorporated herein by reference). One measure of similarity provided by the BLAST algorithm is the minimum total probability (P(N)), which provides an indication of the probability that a match between two nucleotide or amino acid sequences will occur by chance. For example, an amino acid sequence is considered to be similar to a reference amino acid sequence if the minimum total probability in the comparison between the test amino acid and the reference amino acid is less than about 0.1, more preferably less than about 0.01, and most preferably less than about 0.001.

[0210] Variants can also be synthetic, recombinant, or chemically modified polynucleotides or polypeptides isolated or produced using methods well known in the art. Variants may contain conservative or non-conservative amino acid changes, as described below. Polynucleotide changes may result in amino acid substitutions, additions, deletions, fusions, and truncations of the polypeptide encoded by the reference sequence. Variants may also contain amino acid insertions, deletions, or substitutions, including insertions and substitutions of amino acids and other molecules that do not normally occur in the peptide sequence underlying the variant, such as, but not limited to, the insertion of ornithine, which does not normally occur in human proteins. The term "conservative substitution" when describing a polypeptide refers to a change in the amino acid composition of a polypeptide that does not significantly change the activity of the polypeptide. For example, a conservative substitution refers to the replacement of an amino acid residue with a different amino acid residue having similar chemical properties. Conservative amino acid substitutions include the replacement of leucine with isoleucine or valine, aspartic acid with glutamic acid, or threonine with serine.

[0211] As referred to herein, a "conservative amino acid substitution" results from the replacement of one amino acid with another amino acid having similar structural and / or chemical properties, such as replacing leucine with isoleucine or valine, aspartic acid with glutamic acid, or threonine with serine. Thus, a "conservative substitution" of a particular amino acid sequence refers to the substitution of an amino acid that is not critical to the activity of the polypeptide, or the substitution of an amino acid with another amino acid having similar properties (e.g., acidic, basic, positively or negatively charged, polar or non-polar, etc.), such that even the substitution of a critical amino acid 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 acid (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). (Creighton, Proteins, WH, incorporated by reference in its entirety.) (See also Freeman and Company (1984)). In some embodiments, individual substitutions, deletions, or additions that alter, modify, or delete a single amino acid or a small number of amino acids can also be considered "conservative substitutions" if the changes do not reduce the activity of the peptide. Insertions or deletions typically range from about 1 to 5 amino acids. Conservative amino acids can be selected based on the position of the amino acid to be substituted within the peptide, for example, whether the amino acid is on the exterior of the peptide and exposed to solvent, or on the interior and not exposed to solvent.

[0212] In alternative embodiments, conservative amino acid substitutions can be selected, including those appropriate for amino acids within the protein or peptide, for example, suitable conservative substitutions of amino acids that are within the protein or peptide (i.e., amino acids not exposed to solvent) can be used, including, but not limited to, the following conservative substitutions: Y 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, S with A or T, and A and S with G, T or V. In some embodiments, non-conservative amino acid substitutions are also encompassed by the term variant.

[0213] As used herein, the term "selectivity" of a molecule for a first receptor compared to a second receptor refers to the EC 50 The first receptor is the EC 50 For example, an EC50 of 1 nM for the first receptor is 50 and an EC of 100 nM at the second receptor 50 A molecule with the following structure has 100-fold selectivity for the first receptor over the second receptor.

[0214] As will be understood by one of ordinary skill in the art, reference herein to "about" a value or parameter includes (and describes) embodiments directed to the value or parameter itself or having a plus or minus variation of the value in a range of less than 10%, or less than 9%, or less than 8%, or less than 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% from the stated value. For example, a statement referring to "about X" includes the statement "X."

[0215] It should be understood that the aspects and embodiments of the present disclosure described herein include "comprising," "consisting of," and / or "consisting essentially of" aspects and embodiments. As used herein, the singular forms "a," "an," and "the" include plural referents unless otherwise indicated.

[0216] A. GIP receptor agonist peptides In various embodiments of the present disclosure, GIP receptor agonist peptides are provided. Additionally, methods are provided for preventing and / or treating diabetes (e.g., type 2 diabetes), obesity, metabolic syndrome, and emesis in a subject in need thereof. In various embodiments, the methods involve administering a therapeutically effective amount of a GIP receptor agonist peptide to the subject.

[0217] As used herein, a GIP agonist peptide of the present disclosure refers to a peptide that preferentially binds to the GIP receptor compared to other receptors, such as the GLP receptor. In some embodiments, exemplary GIP agonist peptides of the present disclosure have an EC 50 GLP1R / EC 50 Preferably, exemplary GIP receptor agonist peptides have a selectivity ratio (EC), defined as the ratio of GIP receptor agonists to GIP receptor agonists. Preferably, the peptide has a selectivity ratio (EC) of greater than 10, or 100, or 1,000, or 10,000, or about 100 to 1,000,000, or greater. 50 GLP1R / EC 50 It is a GIP agonist peptide when it has GIPR.

[0218] In some embodiments, a GIP receptor agonist peptide or a salt thereof is provided. The GIP receptor agonist peptide has the formula (I): P 1-A1-A2-A3-A4-A5-A6-A7-A8-A9-A10-A11-A12-A13-A14-A15-A16-A17-A18-A19-A20-A21-A2 2-A23-A24-A25-A26-A27-A28-A29-A30-A31-A32-A33-A34-A35-A36-A37-A38-A39-A40-A41-P 2 (SEQ ID NO: 4), or a salt thereof; During the ceremony, P 1 teeth, -R A1 , -CO-R A1 , -CO-OR A1 , -CO-COR A1 , -SO-R A1 , -SO2-R A1 , -SO2-OR A1 , -CO-NR A2 R A3 , -SO2-NR A2 R A3 , -C(=NR A1 )-NR A2 R A3 or represents a group of the formula Does not exist, R A1 , R A2 , and R A3 each independently represents a hydrogen atom, an optionally substituted hydrocarbon group, or an optionally substituted heterocyclic group; P 2 represents -NH2 or -OH, A1 represents Tyr, 3,5-Dix Tyr, D-Tyr, 3,5 di-Br-Tyr, Phe, alpha methyl-Phe, mono-halo-Phe, bis-halo-Phe, -Tyr, -D-Phe, -D-Tyr, des-amino-Phe, or des-amino-Tyr; A2 represents Aib, Ala, Gly, Sar, Abu, or D-Ala; A3 represents Glu or Pro, A4 represents Gly or Ser, A5 represents Thr, D-Iva, Glu, Iva, or Ser; A6 represents Ala, Aib, alpha-methyl-Phe, A6C, Glu, Iva, Arg, Phe, or Val; A7 represents Ile, Lys, Val, Ala, Aib, α-methyl-Leu, A6C, Asp, Phe, Gly, Iva, Leu, Arg, or Ser; A8 represents Ser, Ala, Aib, Asp, Phe, Gly, Leu, or Arg; A9 represents Asp, Leu, Aib, Glu, Asn, Gln, Ser, or Phe; A10 represents Aib, α-methyl-Phe, A6C, Lys, or Tyr; A11 represents Aib Ser, Ala, Glu, Iva, A5c, A6c, or Leu; A12 represents Ile, Ala, Aib, Glu, α-methyl-Phe, Phe, Lys, Arg, Ser, Trp, A6C, Cys, or Asp; A13 represents Aib, Ala, Val, Iva, Gln, Leu, Tyr, D-Iva, alpha methyl-Phe, A6C, or Glu; A14 represents Leu, Nle, Tyr, Ala, Aib, α-methyl-Leu, Lys, Leu, Ser, Met, or Me; A15 represents Ala, Aib, Leu, Asn, Asp, Glu, Lys, Ser, or Tyr; A16 represents Arg, Ala, Aib, Glu, Gly, Leu, Ser, or Lys; A17 represents Aib, Ala, Lys, Asp, Arg, Gln, Glu, or Ile; A18 represents Ala, Aib, A6C, Phe, Gly, Iva, Leu, Ser, Trp, or His; A19 represents Gln, Ala, Val, Aib, Ile, Arg, or Ser; A20 represents Aib, Ala, Arg, Glu, Gly, Ser, Val, or Gln; A21 represents Asn, Asp, Glu, Leu, Ala, Aib, Lys, Gln, or Ser; A22 represents Phe, Glu, Gln, Arg, Trp, or αMePhe; A23 represents Ile, Aib, Asp, Glu, Arg, Thr, or Val; A24 represents Arg, Asn, Asp, Lys, Lys(Ac), Ala, Aib, Cys, Phe, Leu, Nle, Ser, Asp, or Gln; A25 represents Trp, Aib, α-methyl-Leu, A6C, Ile, Asn, Nle, Arg, or Val; A26 represents Aib, Iva, Ala, alpha-methyl-Leu, A6C, Ile, Asn, Nle, Arg, Val, or Leu; A27 is Leu, Val, Ala, Aib, α-methyl-Leu, A6C, Ile, Me represents t, Nle, Arg, Trp, or Ile, A28 represents Ala, Arg, Lys, Aib, Asp, Asn, or Lys(Ac); A29 represents Gln, Gly, Arg, Glu, Leu, or Aib; A30 represents Lys, Arg, Gly, or Glu; A31 represents Pro, Gly, Hyp, Gln, Phe, ψ, or a deletion; A32 represents Ser, Gly, Arg, Lys, ψ, or a deletion; A33 represents Ser, Gly, Pro, Lys, ψ, or a deletion; A34 represents Gly, Ser, Asn, ψ, or a deletion; A35 represents Ala, Ser, Ser, Asp, ψ, or a deletion; A36 represents Pro, Gly, Gly, Hyp, Trp, ψ, or a deletion; A37 represents Pro, Gly, Ala, Hyp, Lys, ψ, or a deletion; A38 represents Pro, Gly, Hyp, His, ψ, or a deletion; A39 represents Ser, Gly, Lys, Pro, Asn, ψ, or a deletion; A40 represents Arg, Ser, Cys, Glu, Lys, Lys-Ac, Pro, Ile, ψ, or a deletion; A41 represents Gly, Ser, Ile, Thr, ψ, or a deletion; Any one or two amino acids selected from A31 to A41 optionally represent ψ, where ψ is a residue independently selected from Lys, Arg, Orn, and Cys, and the side chain of the residue is ψ, provided that the GIP receptor agonist peptide is not a peptide having any one of the amino acid sequences of SEQ ID NOs: 4 to 569 disclosed in PCT / JP2018 / 013540.

[0219] In some embodiments, a GIP receptor agonist peptide or a salt thereof is provided. The GIP receptor agonist peptide is represented by the formula: The GIP receptor agonist peptide is represented by the formula (II): P 1 -Tyr-A2-Glu-Gly-Thr-A6-A7-A8-A9-A10-A11-A12-A13-A14-A15-A16-A17-A18-A19-A20-A21- A22-A23-A24-A25-A26-A27-A28-A29-A30-A31-A32-A33-A34-A35-A36-A37-A38-A39-A40-A41-P 2 (SEQ ID NO: 5) or a salt thereof, wherein: P 1 teeth, -R A1 , -CO-R A1 , -CO-OR A1 , -CO-COR A1 , -SO-R A1 , -SO2-R A1 , -SO2-OR A1 , -CO-NR A2 R A3 , -SO2-NR A2 R A3 ,or -C(=NR A1 )-NR A2 R A3 represents a group represented by the formula: R A1 , R A2 , and R A3 each independently represents a hydrogen atom, an optionally substituted hydrocarbon group, or an optionally substituted heterocyclic group; P 2 represents -NH2 or -OH, A2 represents Aib or D-Ala; A6 represents Iva, Phe, or Val; A7 represents Ile, Lys, or Val; A8 represents Ser, A9 represents Asp, Leu, or Phe; A10 represents Tyr, A11 represents Aib or Ser; A12 represents Ile, A13 represents Aib, Ala, Gln, Leu, Tyr, or D-Iva; A14 represents Leu, A15 represents Asp, Glu, Lys, Ser, or Tyr; A16 represents Arg or Lys; A17 represents Aib, Gln, or Ile; A18 represents Ala or His; A19 represents Gln or Ser; A20 represents Aib, Ala, or Gln; A21 represents Asn, Asp, Glu, Leu, or Ser; A22 represents Phe or αMePhe; A23 represents Ile or Val, A24 represents Arg, Asn, Asp, Lys, or Lys(Ac); A25 represents Trp, A26 stands for Aib, Iva, or Leu, A27 represents Leu, A28 represents Ala, Arg, Lys, or Lys(Ac); A29 represents Gln or Gly; A30 represents Arg or Gly; A31 represents Pro, Gly, ψ, or a deletion; A32 represents Ser, Gly, ψ, or a deletion; A33 represents Ser, Gly, ψ, or a deletion; A34 represents Gly, ψ, or a deletion; A35 represents Ala, Ser, ψ, or a deletion; A36 represents Pro, Gly, ψ, or a deletion; A37 represents Pro, Gly, ψ, or a deletion; A38 represents Pro, Gly, ψ, or a deletion; A39 represents Ser, Gly, ψ, or a deletion; A40 represents Arg, Ser, ψ, or a deletion; A41 represents Gly, ψ, or a deletion; Any one or two amino acids selected from A31 to A41 optionally represent ψ, where ψ is a residue independently selected from Lys, Arg, Orn, and Cys, and the side chain of said residue is ψ, provided that the GIP receptor agonist peptide is not a peptide having any one of the amino acid sequences of SEQ ID NOS: 4 to 569 disclosed in PCT / JP2018 / 013540.

[0220] In some embodiments, a GIP receptor agonist peptide or a salt thereof is provided. The GIP receptor agonist peptide has the formula (III): P 1 -Tyr-A2-Glu-Gly-Thr-A6-A7-A8-A9-A10-A11-A12-A13-A14-A15-A16-A17-A18-A19-A20-A21- A22-A23-A24-A25-A26-A27-A28-A29-A30-A31-A32-A33-A34-A35-A36-A37-A38-A39-A40-A41-P 2 (SEQ ID NO: 6), or a salt thereof, wherein: P 1 teeth, -R A1 , -CO-R A1 , -CO-OR A1 , -CO-COR A1 , -SO-R A1 , -SO2-R A1 , -SO2-OR A1 , -CO-NR A2 R A3 , -SO2-NR A2 R A3 ,or -C(=NR A1 )-NR A2 R A3 represents a group represented by the formula: R A1 , R A2 , and R A3 each independently represents a hydrogen atom, an optionally substituted hydrocarbon group, or an optionally substituted heterocyclic group; P 2 represents -NH2 or -OH, A2 represents Aib or D-Ala; A6 represents Iva, Phe, or Val; A7 represents Ile, Lys, or Val; A8 represents Ser, A9 represents Asp, Leu, or Phe; A10 represents Tyr, A11 represents Aib or Ser; A12 represents Ile, A13 represents Aib, Ala, Gln, Leu, Tyr, or D-Iva; A14 represents Leu, A15 represents Asp, Glu, Lys, Ser, or Tyr; A16 represents Arg or Lys; A17 represents Aib, Gln, or Ile; A18 represents Ala or His; A19 represents Gln or Ser; A20 represents Aib, Ala, or Gln; A21 represents Asn, Asp, Glu, Leu, or Ser; A22 represents Phe or αMePhe; A23 represents Ile or Val, A24 represents Arg, Asn, Asp, Lys, or Lys(Ac); A25 represents Trp, A26 stands for Aib, Iva, or Leu, A27 represents Leu, A28 represents Ala, Arg, Lys, or Lys(Ac); A29 represents Gln or Gly; A30 represents Arg or Gly; A31 represents Pro, Gly, ψ, or a deletion; A32 represents Ser, Gly, ψ, or a deletion; A33 represents Ser, Gly, ψ, or a deletion; A34 represents Gly, ψ, or a deletion; A35 represents Ala, Ser, ψ, or a deletion; A36 represents Pro, Gly, ψ, or a deletion; A37 represents Pro, Gly, ψ, or a deletion; A38 represents Pro, Gly, ψ, or a deletion; A39 represents Ser, Gly, ψ, or a deletion; A40 represents Arg, Ser, ψ, or a deletion; A41 represents Gly, ψ, or a deletion; Any one or two amino acids selected from A31 to A41 optionally represent ψ. where ψ is a residue independently selected from Lys, Arg, Orn, and Cys, and the side chain of the residue is substituted, provided that the GIP receptor agonist peptide is not a peptide having any one of the amino acid sequences of SEQ ID NOs: 4 to 569 disclosed in PCT / JP2018 / 013540.

[0221] In some embodiments, a GIP receptor agonist peptide or a salt thereof is provided. The GIP receptor agonist peptide has formula (IV): P 1 -A1-A2-Glu-Gly-Thr-A6-A7-A8-A9-A10-A11-A12-A13-A14-A15-A16-A17-A18-A19-A20-A21-A 22-A23-A24-A25-A26-A27-A28-A29-A30-A31-A32-A33-A34-A35-A36-A37-A38-A39-A40-A41-P 2 (SEQ ID NO: 7), or a salt thereof, wherein: P 1 teeth, -R A1 , -CO-R A1 , -CO-OR A1 , -CO-COR A1 , -SO-R A1 , -SO2-R A1 , -SO2-OR A1 , -CO-NR A2R A3 , -SO2-NR A2 R A3 ,or -C(=NR A1 )-NR A2 R A3 represents a group represented by the formula: R A1 , R A2 , and R A3 each independently represents a hydrogen atom, an optionally substituted hydrocarbon group, or an optionally substituted heterocyclic group; P 2 represents -NH2 or -OH, A1 represents Tyr, A2 represents Aib or D-Ala; A6 represents Iva, Phe, or Val; A7 represents Ile, Lys, or Val; A8 represents Ser, A9 represents Asp, Leu, or Phe; A10 represents Tyr, A11 represents Aib or Ser; A12 represents Ile, A13 represents Aib, Ala, Gln, Leu, Tyr, or D-Iva; A14 represents Leu, A15 represents Asp, Glu, Lys, Ser, or Tyr; A16 represents Arg or Lys; A17 represents Aib, Gln, or Ile; A18 represents Ala or His; A19 represents Gln or Ser; A20 represents Aib, Ala, or Gln; A21 represents Asn, Asp, Glu, Leu, or Ser; A22 represents Phe or αMePhe; A23 represents Ile or Val, A24 represents Arg, Asn, Asp, Lys, or Lys(Ac); A25 represents Trp, A26 stands for Aib, Iva, or Leu, A27 represents Leu, A28 represents Ala, Arg, Lys, or Lys(Ac); A29 represents Gln or Gly; A30 represents Arg, A31 represents Pro, Gly, ψ, or a deletion; A32 represents Ser, Gly, ψ, or a deletion; A33 represents Ser, Gly, ψ, or a deletion; A34 represents Gly, ψ, or a deletion; A35 represents Ala, Ser, ψ, or a deletion; A36 represents Pro, Gly, ψ, or a deletion; A37 represents Pro, Gly, ψ, or a deletion; A38 represents Pro, Gly, ψ, or a deletion; A39 represents Ser, Gly, ψ, or a deletion; A40 represents Arg, Ser, ψ, or a deletion; A41 represents Gly, ψ, or a deletion; Any one or two amino acids selected from A31 to A41 optionally represent ψ, where ψ is a residue independently selected from Lys, Arg, Orn, and Cys, and the side chain of the residue is substituted, provided that the GIP receptor agonist peptide is not a peptide having any one of the amino acid sequences of SEQ ID NOs: 4 to 569 disclosed in PCT / JP2018 / 013540.

[0222] In some embodiments, a GIP receptor agonist peptide or a salt thereof is provided. The GIP receptor agonist peptide is A1-A2-Glu-Gly-Thr-A6-A7-A8-A9-A10-A11-A12-A13-A14-A15-A16-A17-A18-A19-A20-A21- in formula (I) A22-A23-A24-A25-A26-A27-A28-A29 is Tyr-Aib-Glu-Gly-Thr-Phe-Ile-Ser-Asp-Tyr-Ser-Ile-Ala- The condition is that the peptide is represented by formula (V), which is Leu-Asp-Arg-Aib-His-Gln-Aib-Asn-Phe-Val-Asn-Trp-Iva-Leu-Ala-Gln (sequence number 8), or a salt thereof, and is not a peptide having any one of the amino acid sequences of SEQ ID NOs: 4 to 569 disclosed in PCT / JP2018 / 013540.

[0223] In some embodiments, a GIP receptor agonist peptide or a salt thereof is provided. The GIP receptor agonist peptide has formula (VI): P 1 -Tyr-Aib-Glu-Gly-Thr-Phe-Ile-Ser-Asp-Tyr-Ser-Ile-Ala-Leu-Asp-Arg-Aib-His-Gln-Aib-As n-Phe-Val-Asn-Trp-Iva-Leu-Ala-Gln-A30-A31-A32-A33-A34-A35-A36-A37-A38-A39-A40-A41-P 2 (SEQ ID NO: 9), or a salt thereof; During the ceremony, P 1 teeth, -R A1 , -CO-R A1 , -CO-OR A1 , -CO-COR A1 , -SO-R A1 , -SO2-R A1 , -SO2-OR A1 , -CO-NR A2 R A3 , -SO2-NR A2 R A3 ,or -C(=NR A1 )-NR A2 R A3 represents a group represented by the formula R A1 , R A2 , and R A3 each independently represents a hydrogen atom, an optionally substituted hydrocarbon group, or an optionally substituted heterocyclic group; P 2 represents -NH2 or -OH, A30 represents Arg, A31 represents Pro, Gly, or Lys(R); A32 represents Ser, Gly, or Lys(R); A33 represents Ser, Gly, or Lys(R); A34 represents Gly or Lys(R), A35 represents Ala, Ser, or Lys(R); A36 represents Pro, Gly, or Lys(R); A37 represents Pro, Gly, Lys(R), or a deletion; A38 represents Pro, Gly, Lys(R), or a deletion; A39 represents Ser, Gly, Lys(R), or a deletion; A40 represents Arg, Ser, Lys(R), or a deletion; A41 represents Gly, Lys(R), or a deletion; Any one or two amino acids selected from A31 to A41 optionally represent Lys(R), where (R) represents a substituent, provided that the GIP receptor agonist peptide is not a peptide having any one of the amino acid sequences of SEQ ID NOs: 4 to 569 disclosed in PCT / JP2018 / 013540GIP.

[0224] In some embodiments, a GIP receptor agonist peptide or a salt thereof is provided. The GIP receptor agonist peptide has formula (VII): P 1 -Tyr-Aib-Glu-Gly-Thr-Phe-Ile-Ser-Asp-Tyr-Ser-Ile-Ala-Leu-Asp-Arg-Aib-His-Gln-Ai b-Asn-Phe-Val-Asn-Trp-Iva-Leu-Ala-Gln-A30-A31-A32-A33-A34-A35-A36-A37-A38-A39-P 2 (SEQ ID NO: 10), or a salt thereof, wherein: P 1 teeth, -R A1 , -CO-R A1 , -CO-OR A1 , -CO-COR A1 , -SO-R A1 , -SO2-R A1 , -SO2-OR A1 , -CO-NR A2 R A3 , -SO2-NR A2 R A3 ,or -C(=NR A1 )-NR A2 R A3 represents a group represented by the formula: R A1 , R A2 , and R A3 each independently represents a hydrogen atom, an optionally substituted hydrocarbon group, or an optionally substituted heterocyclic group; P 2 represents -NH2 or -OH, A30 represents Arg, A31 represents Pro, Gly, or Lys(R); A32 represents Ser, Gly, or Lys(R); A33 represents Ser, Gly, or Lys(R); A34 represents Gly or Lys(R), A35 represents Ala, Ser, or Lys(R); A36 represents Pro, Gly, or Lys(R); A37 represents Pro, Gly, Lys(R), A38 represents Pro, Gly, Lys(R), A39 represents Ser, Gly, or Lys(R); Here, any one or two amino acids selected from A31 to A39 optionally represent Lys(R), where (R) represents a substituent or a salt thereof.

[0225] In some embodiments, a GIP receptor agonist peptide or a salt thereof is provided. The GIP receptor agonist peptide has formula (VIII): P 1 -Tyr-Aib-Glu-Gly-Thr-Phe-Ile-Ser-Asp-Tyr-Ser-Ile-Ala-Leu-Asp-Arg-Aib-His-Gln-Aib- Asn-Phe-Val-Asn-Trp-Iva-Leu-Ala-Gln-A30-A31-A32-A33-A34-A35-A36-A37-A38-A39-A40-P 2 (SEQ ID NO: 11), or a salt thereof, wherein: P 1 teeth, -R A1 , -CO-R A1 , -CO-OR A1 , -CO-COR A1 , -SO-R A1 , -SO2-R A1 , -SO2-OR A1 , -CO-NR A2 R A3 , -SO2-NRA2 R A3 ,or -C(=NR A1 )-NR A2 R A3 represents a group represented by the formula: R A1 , R A2 , and R A3 each independently represents a hydrogen atom, an optionally substituted hydrocarbon group, or an optionally substituted heterocyclic group; P 2 represents -NH2 or -OH, A30 represents Arg, A31 represents Pro, Gly, or Lys(R); A32 represents Ser, Gly, or Lys(R); A33 represents Ser, Gly, or Lys(R); A34 represents Gly or Lys(R), A35 represents Ala, Ser, or Lys(R); A36 represents Pro or Lys(R); A37 represents Pro or Lys(R); A38 represents Pro or Lys(R); A39 represents Ser or Lys(R); A40 represents Arg or Ser; Here, any one or two amino acids selected from A31 to A39 optionally represent Lys(R), where (R) represents a substituent or a salt thereof.

[0226] In some embodiments, a GIP receptor agonist peptide or a salt thereof is provided. Formula (I): P 1-A1-A2-A3-A4-A5-A6-A7-A8-A9-A10-A11-A12-A13-A14-A15-A16-A17-A18-A19-A20-A21-A2 2-A23-A24-A25-A26-A27-A28-A29-A30-A31-A32-A33-A34-A35-A36-A37-A38-A39-A40-A41-P 2 A GIP receptor agonist peptide represented by (SEQ ID NO: 4), or a salt thereof, During the ceremony, P 1 teeth, -R A1 , -CO-R A1 , -CO-OR A1 , -CO-COR A1 , -SO-R A1 , -SO2-R A1 , -SO2-OR A1 , -CO-NR A2 R A3 , -SO2-NR A2 R A3 , -C(=NR A1 )-NR A2 R A3 or represents a group of the formula Does not exist, R A1 , R A2 , and R A3 each independently represents a hydrogen atom, an optionally substituted hydrocarbon group, or an optionally substituted heterocyclic group; P 2 represents -NH2 or -OH, A1 represents Tyr, 3,5-Dix Tyr, D-Tyr, 3,5 di-Br-Tyr, Phe, alpha methyl-Phe, mono-halo-Phe, bis-halo-Phe, -Tyr, -D-Phe, -D-Tyr, des-amino-Phe, or des-amino-Tyr; A2 represents Aib, Ala, Gly, Sar, Abu, or D-Ala; A3 represents Glu or Pro, A4 represents Gly or Ser, A5 represents Thr, D-Iva, Glu, Iva, or Ser; A6 represents Ala, Aib, alpha-methyl-Phe, A6C, Glu, Iva, Arg, Phe, or Val; A7 represents Ile, Lys, Val, Ala, Aib, α-methyl-Leu, A6C, Asp, Phe, Gly, Iva, Leu, Arg, or Ser; A8 represents Ser, Ala, Aib, Asp, Phe, Gly, Leu, or Arg; A9 represents Asp, Leu, Aib, Glu, Asn, Gln, Ser, or Phe; A10 represents Aib, α-methyl-Phe, A6C, Lys, or Tyr; A11 represents Aib Ser, Ala, Glu, Iva, A5c, A6c, or Leu; A12 represents Ile, Ala, Aib, Glu, α-methyl-Phe, Phe, Lys, Arg, Ser, Trp, A6C, Cys, or Asp; A13 represents Aib, Ala, Val, Iva, Gln, Leu, Tyr, D-Iva, alpha methyl-Phe, A6C, or Glu; A14 represents Leu, Nle, Tyr, Ala, Aib, α-methyl-Leu, Lys, Leu, Ser, Met, or Me; A15 represents Ala, Aib, Leu, Asn, Asp, Glu, Lys, Ser, or Tyr; A16 represents Arg, Ala, Aib, Glu, Gly, Leu, Ser, or Lys; A17 represents Aib, Ala, Lys, Asp, Arg, Gln, Glu, or Ile; A18 is Ala, Aib, A6C, Phe, Gly, Iva, Leu, Ser, Trp , or His, A19 represents Gln, Ala, Val, Aib, Ile, Arg, or Ser; A20 represents Aib, Ala, Arg, Glu, Gly, Ser, Val, or Gln; A21 represents Asn, Asp, Glu, Leu, Ala, Aib, Lys, Gln, or Ser; A22 represents Phe, Glu, Gln, Arg, Trp, or αMePhe; A23 represents Ile, Aib, Asp, Glu, Arg, Thr, or Val; A24 represents Arg, Asn, Asp, Lys, Lys(Ac), Ala, Aib, Cys, Phe, Leu, Nle, Ser, Asp, or Gln; A25 represents Trp, Aib, α-methyl-Leu, A6C, Ile, Asn, Nle, Arg, or Val; A26 represents Aib, Iva, Ala, alpha-methyl-Leu, A6C, Ile, Asn, Nle, Arg, Val, or Leu; A27 represents Leu, Val, Ala, Aib, alpha-methyl-Leu, A6C, Ile, Met, Nle, Arg, Trp, or Ile; A28 represents Ala, Arg, Lys, Aib, Asp, Asn, or Lys(Ac); A29 represents Gln, Gly, Arg, Glu, Leu, or Aib; A30 represents Lys, Arg, Gly, or Glu; A31 represents Pro, Gly, Hyp, Gln, Phe, ψ, or a deletion; A32 represents Ser, Gly, Arg, Lys, ψ, or a deletion; A33 represents Ser, Gly, Pro, Lys, ψ, or a deletion; A34 represents Gly, Ser, Asn, ψ, or a deletion; A35 represents Ala, Ser, Ser, Asp, ψ, or a deletion; A36 represents Pro, Gly, Gly, Hyp, Trp, ψ, or a deletion; A37 represents Pro, Gly, Ala, Hyp, Lys, ψ, or a deletion; A38 represents Pro, Gly, Hyp, His, ψ, or a deletion; A39 represents Ser, Gly, Lys, Pro, Asn, ψ, or a deletion; A40 represents Arg, Ser, Cys, Glu, Lys, Lys-Ac, Pro, Ile, ψ, or a deletion; A41 represents Gly, Ser, Ile, Thr, ψ, or a deletion; A GIP receptor agonist peptide or a salt thereof, wherein any one or two amino acids selected from A31 to A41 optionally represent ψ, where ψ is a residue independently selected from Lys, Arg, Orn, and Cys, and the side chain of the residue is substituted, provided that the GIP receptor agonist peptide is not a peptide having any one of the amino acid sequences of SEQ ID NOs: 4 to 569 disclosed in PCT / JP2018 / 013540.

[0227] In some embodiments, there is provided a GIP receptor agonist peptide or salt thereof of Formula (II): P1-Tyr-A2-Glu-Gly-Thr-A6-A7-A8-A9-A10-A11-A12-A13-A14-A15- A16-A17-A18-A19-A20-A21-A22-A23-A24-A25-A26-A27-A28-A29-A30-A31-A32-A33-A34-A35-A36-A37-A38-A39-A40- A41-P 2 (SEQ ID NO: 5) or a salt thereof, P 1 teeth, -R A1 , -CO-R A1 , -CO-OR A1 , -CO-COR A1 , -SO-R A1 , -SO2-R A1 , -SO2-OR A1 , -CO-NR A2 R A3 , -SO2-NR A2 R A3 ,or -C(=NR A1 )-NR A2 R A3 represents a group represented by the formula: R A1 , R A2 , and R A3 each independently represents a hydrogen atom, an optionally substituted hydrocarbon group, or an optionally substituted heterocyclic group; P 2 represents -NH2 or -OH, A2 represents Aib or D-Ala; A6 represents Iva, Phe, or Val; A7 represents Ile, Lys, or Val; A8 represents Ser, A9 represents Asp, Leu, or Phe; A10 represents Tyr, A11 represents Aib or Ser; A12 represents Ile, A13 represents Aib, Ala, Gln, Leu, Tyr, or D-Iva; A14 represents Leu, A15 represents Asp, Glu, Lys, Ser, or Tyr; A16 represents Arg or Lys; A17 represents Aib, Gln, or Ile; A18 represents Ala or His; A19 represents Gln or Ser; A20 represents Aib, Ala, or Gln; A21 represents Asn, Asp, Glu, Leu, or Ser; A22 represents Phe or αMePhe; A23 represents Ile or Val, A24 represents Arg, Asn, Asp, Lys, or Lys(Ac); A25 represents Trp, A26 stands for Aib, Iva, or Leu, A27 represents Leu, A28 represents Ala, Arg, Lys, or Lys(Ac); A29 represents Gln or Gly; A30 represents Arg, Gly, ψ, or a deletion; A31 represents Pro, Gly, ψ, or a deletion; A32 represents Ser, Gly, ψ, or a deletion; A33 represents Ser, Gly, ψ, or a deletion; A34 represents Gly, ψ, or a deletion; A35 represents Ala, Ser, ψ, or a deletion; A36 represents Pro, Gly, ψ, or a deletion; A37 represents Pro, Gly, ψ, or a deletion; A38 represents Pro, Gly, ψ, or a deletion; A39 represents Ser, Gly, ψ, or a deletion; A40 represents Arg, Ser, ψ, or a deletion; A41 represents Gly, ψ, or a deletion; Any one or two amino acids selected from A31 to A41 optionally represent ψ, where ψ is a residue independently selected from Lys, Arg, Orn, and Cys. and the side chain of the residue is substituted, provided that the GIP receptor agonist peptide is not a peptide having any one of the amino acid sequences of SEQ ID NOS: 4 to 569 disclosed in PCT / JP2018 / 013540, or a salt thereof.

[0228] In various embodiments, exemplary GIP receptor agonist peptides for use in the methods, compositions, and medicaments exemplified herein have at least 80%, or at least 85%, or at least 90%, or at least 95%, or at least 96%, or at least 97%, or at least 98%, or at least 99%, or 100% sequence identity to any of the GIP receptor agonist peptides defined by formulas (I), (II), (III), (IV), (V), (VI), (VII), and (VIII).

[0229] In various embodiments, exemplary GIP receptor agonist peptides for use in the methods, compositions, and medicaments exemplified herein have 100% sequence identity to any of the GIP receptor agonist peptides defined by formulas (I), (II), (III), (IV), (V), (VI), (VII), and (VIII).

[0230] In various embodiments, the GIP receptor agonist peptides defined by formulas (I), (II), (III), (IV), (V), (VI), (VII), and (VIII) are 2 is defined by the methyl (Me) group.

[0231] With reference to the above-described GIP receptor agonist peptides defined by formulas (I), (II), and (III), in various embodiments, the GIP receptor agonist peptide has at least one 1, 2, or 3 amino acid residues having a bivalent substituent covalently attached to the side chain of the amino acid. For example, in some embodiments, the GIP receptor agonist peptide has an amino acid sequence having at least one amino acid or modified amino acid, such as a Cys, homocysteine, Lys, Orn, Dab, Dap, or p-amine-phenylalanine residue side chain of the GIP receptor agonist peptide covalently attached to a substituent (R). In various embodiments, the Cys, homocysteine, Lys, Orn, Dab, Dap, or p-amine-phenylalanine residue, exemplified herein as "ψ" of the GIP receptor agonist peptide, can be covalently attached to a substituent (R).

[0232] In some embodiments, ψ is a residue independently selected from Lys, Arg, Orn, and Cys, having a substituted side chain. For example, a peptide that is a selective GIP receptor agonist can have a ψ residue substituted with an (R) group. In various embodiments, the (R) group represents XL-, where L represents a bivalent linker. In some embodiments, the bivalent linker can include PEG, Abu-, (Gly)(2-8)-, gGlu(1-3)-, a glycine linker having 1 to 10 amino acid residues, e.g., 2-10, 2-6, or 5-6 linked glycine residues, or a combination of the foregoing linkers. In these embodiments, X represents a substituent group.

[0233] In various embodiments, the GIP receptor agonist peptide may contain one or two ψ residues, e.g., one or two residues from Cys, homocysteine, Lys, Orn, Dab, Dap, or p-amine-phenylalanine, with an XL-substituent, for example. In some embodiments, ψ is a Lys residue and / or a Cys residue, each independently having an XL-substituted side chain. In various embodiments, the GIP receptor agonist peptide may contain one or two ψ residues, e.g., one or two residues from Cys, homocysteine, Lys, Orn, Dab, Dap, or p-amine-phenylalanine, with an XL-substituent, for example. , or one or two residues from p-amine-phenylalanine, and L represents (PEG3)2-, Abu-, (Gly)(2-8)-, gGlu(1-3)-, or a combination thereof, such as (PEG3)2-gGlu-, Abu-gGlu-, (Gly)5-gGlu-, or (Gly)6-gGlu-, GGGGG-, (PEG3)2-, PEG3)2-(Gly)5-6-, or a combination thereof.

[0234] In some embodiments, the GIP receptor agonist peptide has one, one, two, or three ψ residues independently selected from Lys, Arg, Orn, and Cys, and each ψ residue independently has a substituted side chain. For example, the selective GIP agonist peptide can have a ψ residue substituted with XL-, where L represents a bivalent linker as discussed herein, e.g., L can represent a bond or a bivalent substituent, and X represents an optionally substituted hydrocarbon group or a salt thereof. In some embodiments, the bivalent substituent 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 a combination thereof.

[0235] In various embodiments, the GIP receptor agonist peptide can include one, two, or three ψ residues, e.g., one or two residues from the following examples: Cys, homocysteine, Lys, Orn, Dab, Dap, or p-amine-phenylalanine, and each ψ residue can be substituted with an (R) group, defined as an XL-substituent. In some embodiments, ψ is a Lys and / or Cys residue, each independently having a side chain substituted with XL-. In related embodiments, the X moiety of the GIP receptor agonist peptide can be an optionally substituted hydrocarbon. In some embodiments, the X moiety of the XL-substituent is a C6-C 20 Monoacid, C6-C 20 It may contain diacids, acetyl groups, or a combination thereof.

[0236] Some exemplary X moieties can include (Trda:C13 diacid), (Teda:C14 diacid), (Peda:C15 diacid), (Heda:C16 diacid), (Hepda:C17 diacid), (Oda:C18 diacid), or (Eda:C20 diacid) (Ida:C__ diacid).

[0237] In various embodiments, the GIP receptor agonist peptides of Formulas (IV)-(VIII) can have one, two, or three Lys amino acids, each substituted with an (R) group. In some embodiments, at least one Lys amino acid, e.g., one Lys, two Lys, or three Lys residues from amino acid residues 30-41 and 46 of the GIP receptor agonist peptide, can be substituted with an (R) group and designated as "Lys(R)." In various embodiments, the (R) group is also defined as XL-, as discussed above with respect to the aforementioned ψ residues associated with the GIP receptor agonist peptides of Formulas (I)-(III). In some embodiments, the L portion of the XL- group can comprise a bivalent linker. In some examples, the bivalent linker can be PEG, Abu-, (Gly) (2-8) -, gGlu (1-3)-, 1 to 10 amino acids, or a combination thereof. In these examples of XL, X can represent a substituent.

[0238] In some embodiments, (R) represents XL-, and L is (PEG3)2-, Abu-, (Gly) (2-8) -, gGlu (1-3) In some embodiments, L represents (PEG3)2-gGlu-, Abu-gGlu-, (Gly)5-gGlu, (Gly)6-gGlu-, GGGGG-, GGGGGG-, (PEG3)2-, or (PEG3)2-(Gly) 5-6- Represents.

[0239] In some related embodiments, L represents a bond or a divalent substituent, and X is optionally The optionally substituted hydrocarbon group or salt thereof. For example, an exemplary GIP receptor agonist peptide has an (R) group, where X is a divalent substituent 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 a combination thereof.

[0240] In some embodiments, an exemplary Lys(R) can include an (R) group defined as an XL- group, where the divalent substituent X is C6-C 20 Monoacid, C6-C 20 diacid, or an acetyl group. Some exemplary X moieties can include: (Trda: C13 diacid), (Teda: C14 diacid), (Peda: C15 diacid), (Heda: C16 diacid), (Hepda: C17 diacid), (Oda: C18 diacid), or (Eda: C20 diacid) (Ida: C__ diacid).

[0241] In some embodiments, exemplary GIP receptor agonist peptides of Formulas (I), (II), (III), (IV), (V), (VI), (VII), and (VIII) can include peptides having one, two, or three amino acids selected from A31-A41, where the ψ or Lys(R) residue has a substituted side chain defined by XL-. In exemplary embodiments, the XL- group of the ψ or Lys(R) residue is: -(g-Glu)2-Oda, -(g-Glu)2-Eda, -(g-Glu)2-Heda, -(PEG3)2-gGlu-Eda, -(PEG3)2-gGlu-Heda, -(PEG3)2-gGlu-Oda, -(PEG3)2-gGlu-Ida, -(PEG3)-gGlu-Eda, -(PEG3)-gGlu-Heda , -(PEG3)-gGlu-Oda, -Abu-gGlu-Oda, -(Gly)5-gGlu-Eda, -(Gly)5-gGlu-Heda, -(Gly)5-gGlu-Oda, -(Gly)5-Heda, -(Gly)5-Oda, -(Gly)5-Eda, -(PEG3)2-Heda, -(PEG3)2-Eda, -(PEG3)2-Oda, or a combination thereof.

[0242] In various embodiments, a Cys, homocysteine, Lys, Orn, Dab, Dap, or p-amine-phenylalanine residue of a GIP receptor agonist peptide can be covalently linked to a substituent, such as a bivalent substituent. In some embodiments, a Cys, homocysteine, Lys, Orn, Dab, Dap, or p-amine-phenylalanine residue of a GIP receptor agonist peptide can be covalently linked to an (R) group. In some illustrative examples, the (R) group can be covalently linked to the side chain of a Lys amino acid. In some examples, an illustrative (R) group represents XL-, where L represents a bivalent linker comprising PEG and / or two or more amino acids, and X represents a substituent or a salt thereof.

[0243] In various embodiments, the GIP receptor agonist peptide of formula (I) to (VIII) or a salt thereof has one or two Lys(R), a residue located at a position between A31 and A41, where (R) represents a substituent, provided that the GIP receptor agonist peptide is not a peptide having the amino acid sequence of any one of SEQ ID NOS: 4 to 569 disclosed in PCT / JP2018 / 013540.

[0244] More preferably, R represents XL-, where L is one or a combination of one or more selected from 2 to 9 linked glycine(s) or glycine linkers containing a single bond, and X represents a C6-C20 mono- or di-acid, or an acetyl group.

[0245] In some embodiments, R represents XL-, where XL- is preferably Trda-GGGG- (Trda:C13 diacid), Trda-GGGGG-, Trda-GGGGGG-, Teda-GGGG- (Teda:C14 diacid), Teda-GGG GG-, Teda-GGGGGG-, Peda-GGGG-(Peda:C15 diacid), Peda-GGGGG-, Peda-GGGGGG-, Heda-GGGG-(Heda:C16 diacid), Heda-GGGGG-, Heda-GGGGGG-, Hepda-GGGG-(Hepda:C17 diacid) acid), Hepda-GGGGG-, Hepda-GGGGGG-, Oda-GGGG-(Oda:C18 diacid), Oda-GGGGG-, Oda-GGGGGG-, Eda-GGGG-(Eda:C20 diacid), Eda-GGGGG-, Eda-GGGGGG-, Eda-GGGGGGGGGG-.

[0246] Alternatively, in some embodiments, (R) represents XL-, where L represents a glycine linker comprising 4, 5, or 6 linked glycines, and X represents a C16-C20 linear saturated dicarboxylic acid.

[0247] In various embodiments, in each example of the GIP receptor agonist peptide of formulas (I) to (VIII), at least one amino acid between A31 and A41, or between A30 and A40, or between A30 and A39 is Lys(R), where (R) represents XL-, L represents a bivalent linker L, and L is (PEG3)2-, Abu-, (Gly) (2-10) -, gGlu (1-3) -, or a combination 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 in which about 2 to about 10 glycines are linked, or in which about 2 to about 7 glycines are linked. In some examples, L represents (Gly) 5-6 -, or (Gly)5-, GGGGG-, or GGGGG-gGlu-. In some embodiments, L represents (PEG3)2-. In some embodiments, L represents (Gly) 2-10 -, -e.g., (Gly) (5-6) In some further embodiments, L represents one or more PEG molecules substituted with the glycine peptide Gly 2-10 For example, L represents a combination of groups such as (PEG3)2-(Gly) 5-6 -, or (PEG3)2-(Gly)5-. In some related embodiments, (R) represents XL-, L represents a bond or a divalent substituent, and X represents an optionally substituted hydrocarbon group, or a salt thereof. In various embodiments relating to examples of various L moieties, (R) represents XL, L is discussed above, and X is a C6-C 20 Monoacid, C6-C 20 diacid, or an acetyl group. For example, in some embodiments, X is (Trda:C13 diacid), (Teda:C14 diacid), (Peda:C15 diacid), (Heda:C16 diacid), (Hepda:C17 diacid), (Oda:C18 diacid), (Eda:C20 diacid), or (Ida:C__ diacid).

[0248] In some embodiments, (R) represents XL-, and L is a bivalent linker comprising or consisting of PEG and / or one or more amino acids, e.g., Gly 2-10- (R) represents a linker, and X represents a substituent. As long as Lys can be linked to the substituent, known PEG linkers, amino acid linkers, or combinations thereof can be used as illustrative examples of bivalent linkers. Alternatively, in some embodiments, (R) represents XL-, L represents a bond or a bivalent substituent, and X represents an optionally substituted hydrocarbon group or a salt thereof. Known bivalent substituents include, but are not limited to, alkylene groups, carbonyl groups, oxycarbonyl groups, imino groups, alkylimino groups, sulfonyl groups, oxy groups, sulfide groups, ester bonds, amide bonds, and carbonate bonds, or combinations thereof can be used.

[0249] In some embodiments, L is (PEG3)2-, Abu-, (Gly) (2-10) -, gGlu (1-3) -, or a combination thereof. In some embodiments, L represents (PEG3)2-gGlu-. In some examples, L represents Abu-gG In some embodiments, L represents a glycine peptide in which about 2 to about 10 glycines are linked, or in which about 2 to about 7 glycines are linked. In some examples, L represents (Gly) 5-6 -, or (Gly)5-, GGGGG-, or GGGGG-gGlu-.

[0250] In some embodiments, L represents (PEG3)2-. In some embodiments, L represents (Gly) 2-10 -, -e.g., (Gly) (5-6) In some further embodiments, L represents the glycine peptide Gly 2-10 L represents a combination of groups such as one or more PEG molecules linked to (PEG)-(Gly), for example, L may be (PEG)-(Gly).5-6 -, or (PEG3)2-(Gly)5-.

[0251] In some embodiments, the (R) group attached to an amino acid, e.g., Cys, homocysteine, Lys, Orn, Dab, Dap, or p-amine-phenylalanine residue, represents XL-, where L represents a bivalent linker comprising or consisting of PEG and / or one or more amino acids, and X represents a substituent. Known PEG linkers, amino acid linkers, or combinations thereof can be used as bivalent linkers as long as they can link Cys, homocysteine, Lys, Orn, Dab, Dap, or p-amine-phenylalanine residues to a substituent. Alternatively, preferably, (R) represents XL-, L represents a bond or a bivalent substituent, and X represents an optionally substituted hydrocarbon group or a salt thereof. Known divalent substituents can be used, including, but not limited to, alkylene groups, carbonyl groups, oxycarbonyl groups, imino groups, alkylimino groups, sulfonyl groups, oxy groups, sulfide groups, ester bonds, amide bonds, carbonate bonds, or combinations thereof. More preferably, (R) represents XL- and L is [ka] a glycine linker containing 1 or 2 to 9 linked glycines or a single bond, and X is selected from the group consisting of C6-C 20In some embodiments, the linker L can be covalently attached to the side chain of at least one amino acid or modified amino acid, e.g., a Cys, homocysteine, Lys, Orn, Dab, Dap, or p-amine-phenylalanine residue of the GIP receptor agonist peptide, which is covalently attached to a substituent (R). In one embodiment, the selective GIP receptor agonist peptide is covalently attached to the (R) group, which is a hydrophilic polymer at any amino acid position from A16 to the C-terminus. In one embodiment, the selective GIP receptor agonist peptide is covalently attached to a hydrophilic polymer at amino acid positions A31-A41. For example, the hydrophilic polymer can be attached to the side chain of a Cys, homocysteine, Lys, Orn, Dab, Dap, or p-amine-phenylalanine residue of the selective GIP receptor agonist peptide. In one embodiment, the hydrophilic polymer is polyethylene glycol (PEG). For example, PEG has a molecular weight of about 1,000 to about 40,000 daltons, for example, about 5,000 to about 40,000 daltons, preferably about 1,000 daltons, or 5,000 daltons, or 10,000 daltons, or 12,000 daltons, or 14,000 to about 20,000 daltons. In some embodiments, the linker L is a PEG molecule, e.g., 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 a substituted ψ residue (R) group, e.g., Cys, homocysteine, Lys, Orn, Dab, Dap, or p-amine-phenylalanine residue, e.g., located at one or more of A30-A41, e.g., A30-A40, or A30-A39. The MPEG linker can include one or more of the following additional MPEG linkers: [ka] In some embodiments, an exemplary MPEG linker that can be used to couple substituent X to a Cys amino acid can include an MPEG molecule having a weight average molecular weight of about 5-30 kDa. In some embodiments, an exemplary PEG linker for attachment to a Cys side chain can include: [ka]

[0252] In various examples, R represents XL-, where XL- is preferably Trda-GGGG- (Trda: C13 diacid), Trda-GGGGG-, Trda-GGGGGG-, Teda-GGGG- (Teda: C14 diacid), Teda-GGGGG-, T eda-GGGGGG-, Peda-GGGG-(Peda:C15 diacid), Peda-GGGGG-, Peda-GGGGGG-, Heda-GGGG-(Heda:C16 diacid), Heda-GGGGG-, Heda-GGGGGG-, Hepda-GGGG-(Hepda:C17 diacid), Represents Hepda-GGGGG-, Hepda-GGGGGG-, Oda-GGGG-(Oda:C18 diacid), Oda-GGGGG-, Oda-GGGGGG-, Eda-GGGG-(Eda:C20 diacid), Eda-GGGGG-, Eda-GGGGGG-, Eda-GGGGGGGG-.

[0253] Alternatively, and particularly preferably, the (R) group represents XL-, where L represents a glycine linker containing five or six linked glycines, and X is C 16 -C 20 It represents a linear saturated dicarboxylic acid.

[0254] Alternatively, and particularly preferably, the (R) group represents XL-, L represents a bond or a divalent substituent, and X represents a C12-C20 fatty acid, or a C12-C20 acylated fatty acid or a salt thereof. In some embodiments, X represents a palmitic fatty acid used to add a palmitoyl group to the epsilon amine side group of a Cys, homocysteine, Lys, Orn, Dab, Dap, or p-amine-phenylalanine residue, e.g., a Lys residue, of a GIP receptor agonist peptide.

[0255] In other embodiments, the GIP receptor agonist peptide has one, two, or three modified lysine residues, i.e., Lys(R), where the (R) group represents XL-, L represents a glycine linker comprising three, four, five, or six linked glycines, and X is a C6-C 20 In one embodiment, the acyl group is a C6-C 20 fatty acyl groups, such as palmitoyl or myristoyl fatty acyl groups.

[0256] In one embodiment, the GIP receptor agonist peptide is covalently attached to an (R) group, which is a hydrophilic polymer at any amino acid position from A30 through the C-terminus. In one embodiment, the GIP receptor agonist peptide is covalently attached to a hydrophilic polymer at amino acid positions A31, A32, A30, A33, A34, A35, A36, A37, A38, A39, A40, A41, or a combination thereof, e.g., positions A31-A41 or A31-A39. For example, the hydrophilic polymer can be attached to the side chain of Cys, homocysteine, Lys, Orn, Dab, Dap, or p-amine-phenylalanine of the GIP receptor agonist peptide. In one embodiment, the hydrophilic polymer is polyethylene glycol (mPEG). The mPEG polymer can also be attached to a glycine linker, i.e., (Gly) (2-8) -, or one or more gGlu- residues, e.g., gGlu (1-3)In some embodiments, the mPEG has a weight average molecular weight of about 1,000 daltons to about 60,000 daltons, e.g., about 5,000 daltons to about 40,000 daltons, preferably 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.

[0257] In some embodiments, methods for conjugating polyethylene glycol (mPEG) polymers to reactive amine or sulfhydryl groups are well known in the art. For example, mPEG can be conjugated to lysine amine side chains using an amine-reactive PEGylation crosslinker. A bis(succinimidyl)penta(ethylene glycol) spacer arm can be used as a homobifunctional amine-to-amine crosslinker, containing an N-hydroxysuccinimide (NHS) ester at both ends of the mPEG spacer arm. Amine-reactive crosslinkers containing a PEG spacer arm. A bis-succinimide ester-activated mPEG compound can be used to crosslink between primary amines (-NH2) in the GIP receptor agonist peptides of the present disclosure. Either the mPEG spacer The N-hydroxysuccinimide ester (NHS) group at the end of the PEG reacts specifically and efficiently with lysine and N-terminal amino groups at pH 7-9 to form stable amide bonds. Other homobifunctional sulfhydryl-reactive crosslinkers containing a maleimide group at either end of the PEG spacer can be used to attach PEG to the Cys amino acid of a GIP receptor agonist peptide. Heterofunctional crosslinking spacer arms can also be used when two different reactive groups, such as an amine group and a sulfhydryl group, are used as linking groups. Sulfhydryl-reactive crosslinkers containing a PEG spacer arm can be used to attach PEG polymers to GIP receptor agonist peptides. In some embodiments, bismaleimide-activated PEG compounds can be used for crosslinking between sulfhydryl (-SH) groups in proteins and other thiol molecules. The maleimide group at either end of the PEG spacer can react specifically and efficiently with reduced sulfhydryls at pH 6.5-7.5 to form stable thioether bonds. In other embodiments, direct attachment of PEG molecules to GIP receptor agonist peptides can be achieved using methods known in the art. For example, a well-known technique is to covalently modify peptides with PEG groups, which requires a PEG compound containing a reactive or targetable functional group at one end. The simplest method for PEGylating peptides rich in surface primary amines is to use a PEG compound containing an NHS ester group at one end, such as methyl-(PEG)n-NHS ester. Similarly, methyl-(PEG)n-maleimide (where n can range from 20 to 300) can be used to attach PEG molecules to Cys-containing peptides of the present disclosure. Methods known in the art for conjugating polyethylene glycol polymers of various lengths, ranging from 1,000 daltons to 20,000 daltons or longer, are described in, for example, Hermanson, GT (2013). 3rd Edition. Bioconjugate Techniques, Academic Press, Veronese, F. and Harris, JM 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 Zalipsky (1995) Advanced Drug Reviews 16:157-182, the entire disclosures of which are incorporated herein by reference in their entireties.

[0258] In various embodiments, the GIP receptor agonist peptides disclosed herein, e.g., for use in the preparation of a medicament, a composition, or for use in the prevention and / or treatment of a condition or disorder, or for use in the methods of prevention and / or treatment disclosed herein represented by the GIP receptor agonist peptide, have an amino acid sequence as provided in any one of Formulas (I), (II), (III), (IV), (V), (VI), (VII), and (VIII), with the proviso that the GIP receptor agonist peptide having the amino acid sequence of any one of Formulas (I), (II), (III), (IV), (V), (VI), (VII), and (VIII) does not have an amino acid sequence as disclosed in any of the peptides having the amino acid sequences of SEQ ID NOs: 4-569 disclosed in International PCT Application No. PCT / JP2018 / 013540, filed March 30, 2018.

[0259] In various embodiments, exemplary compounds having a structure defined in any one of formulas (I), (II), (III), (IV), (V), (VI), (VII), and (VIII) are GIP receptor agonist peptides are shown in FIG.

[0260] B. Synthetic GIP Agonist Peptides GIP receptor agonist peptides can be synthesized recombinantly or produced according to peptide synthesis methods known in the art. Peptide synthesis methods can be, for example, solid-phase synthesis or liquid-phase synthesis. That is, the desired GIP receptor agonist peptide can be produced by repeatedly condensing a partial peptide or amino acid capable of constituting the GIP receptor agonist peptide with the remaining portion of the desired sequence (which may be composed of two or more amino acids). If the product having the desired sequence has a protecting group, the desired GIP receptor agonist peptide can be produced by removing the protecting group. Examples of known methods for condensing and removing protecting groups include the methods described below in (1) to (5). (1) M. Bodanszky and MA 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.

[0261] After the reaction, the GIP receptor agonist peptide can be purified and isolated using a combination of conventional purification methods such as solvent extraction, distillation, column chromatography, liquid chromatography, recrystallization, etc. If the peptide obtained by the above method is in free form, it can be converted into a suitable salt by a known method. Conversely, if the peptide is obtained in the form of a salt, the salt can be converted into the free form or another salt by a known method.

[0262] The starting compound may also be a salt. Examples of such salts include those exemplified as salts of the exemplary selective GIP agonists described below.

[0263] For the condensation of protected amino acids or peptides, various activating reagents can be used in peptide synthesis, particularly preferably trisphosphonium salts, tetramethyluronium salts, carbodiimides, etc. Examples of trisphosphonium salts include benzotriazol-1-yloxytris(pyrrolidino)phosphonium hexafluorophosphate (PyBOP), bromotris(pyrrolidino)phosphonium hexafluorophosphate (PyBroP), and 7-azabenzotriazol-1-yloxytris(pyrrolidino)phosphonium hexafluorophosphate (PyAOP). Examples of tetramethyluronium salts include 2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (HBTU), 2-(7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (HATU), and 2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (HATU). Examples of the carbodiimide include 3,3-tetramethyluronium tetrafluoroborate (TBTU), 2-(5-norbornane-2,3-dicarboximido)-1,1,3,3-tetramethyluronium tetrafluoroborate (TNTU), and O-(N-succimidyl)-1,1,3,3-tetramethyluronium tetrafluoroborate (TSTU). Examples of the carbodiimide include N,N'-dicyclohexylcarbodiimide (DCC), N,N'-diisopropylcarbodiimide (DIPCDI), and N-ethyl-N'-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDCI·HCl). In the case of condensation using these, a racemization inhibitor (e.g., N-hydroxy-5-norbornene-2,3-dicarboxylic acid imide (HONB), 1-hydroxybenzotriazole (HOBt), 1-hydroxy-7-azabenzotriazole (HOAt), 3,4-dihydro-3-hydroxy-4-oxo-1,2,3-benzotriazine (HOOBt), 2-cyano-2-(hydroxyimino)ethyl acetate (Oxyma), etc.) is preferred. The solvent used in the condensation can be appropriately selected from solvents known to be usable in peptide condensation reactions. Examples of suitable solvents include anhydrous or hydrous N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidone, and other acidic amides; halogenated hydrocarbons such as methylene chloride and chloroform; alcohols such as trifluoroethanol and phenol; sulfoxides such as dimethyl sulfoxide; tertiary amines such as pyridine; ethers such as dioxane and tetrahydrofuran; nitriles such as acetonitrile and propionitrile; esters such as methyl acetate and ethyl acetate; and appropriate mixtures of these. The reaction temperature is appropriately selected from the range known to be suitable for peptide coupling reactions, typically between approximately -20°C and 90°C. Activated amino acid derivatives are typically used in a 1.5- to 6-fold excess. In solid-phase synthesis, if condensation is found to be insufficient in a ninhydrin reaction test, sufficient condensation can be achieved by repeating the condensation reaction without removing the protecting group. If condensation is still insufficient after repeated reactions, the unreacted amino acid can be acylated with acetic anhydride, acetylimidazole, or other suitable solvents to avoid adverse effects on subsequent reactions.

[0264] Examples of protecting groups for the amino group of the starting amino acid include benzyloxycarbonyl (Z), tert-butoxycarbonyl (Boc), tert-pentyloxycarbonyl, isobornyloxycarbonyl, 4-methoxybenzyloxycarbonyl, 2-chlorobenzyloxycarbonyl (Cl-Z), 2-bromobenzyloxycarbonyl (Br-Z), adamantyloxycarbonyl, trifluoroacetyl, phthaloyl, formyl, 2-nitrophenylsulfenyl, diphenylphosphinothioyl, 9-fluorenylmethyloxycarbonyl (Fmoc), trityl, and the like.

[0265] Examples of carboxyl protecting groups for the starting amino acid include those listed above. 1-6 Alkyl group, C 3-10 Cycloalkyl groups, C 7-14 In addition to aralkyl groups, radicals include aryl, 2-adamantyl, 4-nitrobenzyl, 4-methoxybenzyl, 4-chlorobenzyl, phenacyl, and benzyloxycarbonyl hydrazide, tert-butoxycarbonyl hydrazide, trityl hydrazide, and the like.

[0266] The hydroxyl groups of serine or threonine can be protected, for example, by esterification or etherification. Examples of groups suitable for esterification include lower (C 2~4 ) alkanoyl groups, aroyl groups such as benzoyl groups, and groups derived from organic acids. Examples of groups suitable for etherification include benzyl, tetrahydropyranyl, tert-butyl (Bu t ), trityl (Trt), etc.

[0267] Examples of the protecting group for the phenolic hydroxyl group of tyrosine include Bzl, 2,6-dichlorobenzyl, 2-nitrobenzyl, Br-Z, tert-butyl, and the like.

[0268] An example of a protecting group for the imidazole of histidine is p-toluenesulfonyl (Tos). , 4-methoxy-2,3,6-trimethylbenzenesulfonyl (Mtr), dinitrophenyl (DNP), benzyloxymethyl (Bom), tert-butoxymethyl (Bum), Boc, Trt, Fmoc, and the like.

[0269] Examples of protecting groups for the guanidino group of arginine include Tos, Z, 4-methoxy-2,3,6-trimethylbenzenesulfonyl (Mtr), p-methoxybenzenesulfonyl (MBS), 2,2,5,7,8-pentamethylchroman-6-sulfonyl (PMC), mesitylene-2-sulfonyl (MTS), 2,2,4,6,7-pentamethyldihydrobenzofuran-5-sulfonyl (Pbf), Boc, Z, NO2, and the like.

[0270] Examples of the protecting group for the 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.

[0271] Examples of the protecting group for the indolyl of tryptophan include formyl (For), Z, Boc, Mts, Mtr, and the like.

[0272] Examples of protecting groups for asparagine and glutamine include Trt, xanthyl (Xan), 4,4'-dimethoxybenzhydryl (Mbh), 2,4,6-trimethoxybenzyl (Tmob), and the like.

[0273] Examples of activated carboxyl groups in the starting materials include the corresponding acid anhydrides, azides, active esters [esters with alcohols (e.g., pentachlorophenol, 2,4,5-trichlorophenol, 2,4-dinitrophenol, cyanomethyl alcohol, paranitrophenol, HONB, N-hydroxysuccinimide, 1-hydroxybenzotriazole (HOBt), 1-hydroxy-7-azabenzotriazole (HOAt)], etc. Examples of activated amino groups in the starting materials include the corresponding phosphorus amides.

[0274] Examples of methods for removing (eliminating) protecting groups include catalytic reduction with a hydrogen stream in the presence of a catalyst such as Pd-black or Pd-carbon; 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 thereof; base treatment using diisopropylethylamine, triethylamine, piperidine, piperazine, or the like; and reduction with sodium in liquid ammonia. The elimination reaction by acid treatment described above is generally carried out at temperatures between -20°C and 40°C. Acid treatment is efficiently carried out by adding cation scavengers such as anisole, phenol, thioanisole, meta-cresol, and para-cresol; or dimethyl sulfide, 1,4-butanedithiol, 1,2-ethanedithiol, or triisopropylsilane. The 2,4-dinitrophenyl group used as a protecting group for the imidazole moiety of histidine can be removed by treatment with thiophenol, and the formyl group used as a protecting group for the indole moiety of tryptophan can be removed by deprotection with acid treatment in the presence of 1,2-ethanedithiol, 1,4-butanedithiol, or the like, or by alkali treatment with dilute sodium hydroxide, dilute ammonia, or the like.

[0275] Protection of a functional group that must not be involved in the reaction between a starting material and a protecting group, removal of the protecting group, activation of a functional group that is involved in the reaction, etc. can be appropriately selected from known protecting groups and known means.

[0276] In the method for preparing amides of peptides, it is necessary to use a resin for amide synthesis. Alternatively, the α-carboxyl group of the carboxy-terminal amino acid is amidated, and the peptide chain is elongated toward the amino group to the desired chain length. Subsequently, a peptide in which only the protecting group at the N-terminal α-amino group of the peptide chain has been removed and a peptide in which only the protecting group at the C-terminal carboxyl group of the peptide chain has been removed are prepared, and both peptides are condensed in the above-mentioned mixed solvent. Details of the condensation reaction are the same as those described above. After purifying the protected peptide obtained by condensation, all protecting groups are removed by the above-mentioned method to obtain the desired crude polypeptide. The crude peptide can be purified using various known purification methods, and the major fraction can be lyophilized to prepare the desired amide of the peptide.

[0277] When the GIP receptor agonist peptide exists as a configurational isomer, conformational isomer, etc., such as an enantiomer or diastereomer, they are also included in the description of the GIP receptor agonist peptide, and each can be isolated by a means known per se or, if necessary, by the above-mentioned separation and purification methods. Furthermore, when the GIP receptor agonist peptide is in the form of a racemate, it can be separated into S-form and R-form by conventional optical resolution.

[0278] When a GIP receptor agonist peptide includes stereoisomers, both the isomers alone and mixtures of the isomers are encompassed within the meaning of the GIP receptor agonist peptide. The GIP receptor agonist peptide can be chemically modified using a substituent and polyethylene glycol according to a method known per se. For example, a chemically modified GIP receptor agonist peptide can be produced by introducing a substituent and / or a covalently bonded polyethylene glycol to a Cys residue, an Asp residue, a Glu residue, a Lys residue, etc., of the GIP receptor agonist peptide. Furthermore, a linker structure may exist between the amino acid of the GIP receptor agonist peptide and the substituent and polyethylene glycol.

[0279] GIP receptor agonist peptides modified with substituents and / or polyethylene glycol (PEG) produce one or more effects related to, for example, enhanced biological activity, increased blood circulation time, reduced immunogenicity, increased solubility, and increased metabolic resistance of therapeutically and diagnostically important peptides.

[0280] The molecular weight of PEG is not particularly limited, and is generally about 1K to about 1000K daltons, preferably about 10K to about 100K daltons, and more preferably about 20K to about 60K daltons.

[0281] Modification of the selective GIP agonists of the present disclosure by adding an (R) substituent can be carried out by introducing the (R) substituent based on known oxidation and reduction reactions.

[0282] Methods well known in the art can be used to modify GIP receptor agonist peptides with PEG, for example, in addition to the exemplary methods described above, the methods described below can be used. (1) A PEGylation reagent having an active ester (for example, SUNBRIGHT MEGC-30TS (trade name), NOF Corp.) is bound to the amino group of the GIP receptor agonist peptide. (2) An aldehyde-containing PEGylation reagent (eg, SUNBRIGHT ME-300AL (trade name), NOF Corp.) is coupled to the amino group of the GIP receptor agonist peptide. (3) Bivalent cross-linking reagents (e.g., GMBS (Dojindo Laboratories), EMCS (Dojindo Laboratories), KMUS (Dojindo Laboratories)) A PEG-10 ... (4) A thiol group is introduced into the GIP receptor agonist peptide via an SH-introducing agent (e.g., D-cysteine ​​residue, L-cysteine ​​residue, Traut's reagent), and this thiol group is reacted with a PEGylation reagent having a maleimide group (e.g., SUNBRIGHT ME-300MA (trade name), NOF Corp.). (5) A thiol group is introduced into the GIP receptor agonist peptide via an SH-introducing agent (e.g., D-cysteine ​​residue, L-cysteine ​​residue, Traut's reagent), and this thiol group is reacted with a PEGylation reagent having an iodoacetamide group (e.g., SUNBRIGHT ME-300IA (trade name), NOF Corp.). (6) As a linker to the N-terminal amino group of the GIP receptor agonist peptide, an ω-aminocarboxylic acid, an α-amino acid, or the like is introduced, and the amino group derived from this linker is reacted with a PEGylation reagent having an active ester, for example, SUNBRIGHT MEGC-30TS (trade name), NOFCorp. ( (7) An ω-aminocarboxylic acid, an α-amino acid, or the like is introduced as a linker to the N-terminal amino group of the GIP receptor agonist peptide, and the amino group derived from this linker is reacted with a PEGylation reagent having an aldehyde group (e.g., SUNBRIGHT ME-300AL (trade name), NOFCorp.).

[0283] Additionally, the GIP receptor agonist peptides can be solvated (eg, hydrated) or non-solvated (eg, non-hydrate).

[0284] The GIP receptor agonist peptide may be isotopically modified (e.g., 3 H, 14 C. 35 S, 125 I) or the like.

[0285] Furthermore, GIP receptor agonist peptides 1 H 2 It may also be a deuterium exchange product that is converted to H(D).

[0286] In some embodiments, isotope-labeled or substituted GIP receptor agonist peptides can be used, for example, as tracers used in positron emission tomography (PET) (PET tracers), and are useful in fields such as medical diagnostics.

[0287] For the GIP receptor agonist peptides referred to herein, the left end is the N-terminus (amino terminus) and the right end is the C-terminus (carboxyl terminus) according to conventional peptide marking. The C-terminus of a peptide can be an amide (-CONH), a carboxyl group (-COOH), a carboxylate (-COO), or a carboxylate (-COOH). - ), alkylamide (-CONHR a ), ester (-COOR a ) In particular, amide (—CONH2) is preferred.

[0288] The GIP receptor agonist peptides of the present disclosure may be in the form of a salt. Examples of such salts include metal salts, ammonium salts, salts with organic bases, salts with inorganic acids, salts with organic acids, salts with basic or acidic amino acids, etc.

[0289] Preferred examples of metal salts include alkali metal salts such as sodium salts and potassium salts, alkaline earth metal salts such as calcium salts, magnesium salts and barium salts, and ammonium salts.

[0290] Preferred examples of salts with organic bases include trimethylamine, triethylamine, pyridine, Examples of salts include salts with ethanolamine, picoline, 2,6-lutidine, ethanolamine, diethanolamine, triethanolamine, cyclohexylamine, dicyclohexylamine, N,N-dibenzylethylenediamine, and the like.

[0291] Preferred examples of salts with inorganic acids include salts with hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid, and the like.

[0292] Preferred examples of salts with organic acids 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.

[0293] Preferred examples of salts with basic amino acids include salts with arginine, lysine, ornithine, etc. Preferred examples of salts with acidic amino acids include salts with aspartic acid, glutamic acid, etc.

[0294] Among the above-mentioned salts, preferred is pharmaceutically acceptable salt.For example, when compound has acidic functional group, preferred is inorganic salt such as alkali metal salt (for example, sodium salt, potassium salt, etc.), alkaline earth metal salt (for example, calcium salt, magnesium salt, barium salt, etc.), ammonium salt, etc.; when compound has basic functional group, preferred is inorganic acid salt such as hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid, etc., or organic acid salt such as acetic acid, phthalic acid, fumaric acid, oxalic acid, tartaric acid, maleic acid, citric acid, succinic acid, methanesulfonic acid, p-toluenesulfonic acid, etc.

[0295] In some embodiments, the GIP receptor agonist peptides may be synthesized and / or used in the form of a prodrug to treat or prevent diseases of the present disclosure, such as diabetes, obesity, and / or emesis. A prodrug refers to a compound that is converted into a GIP receptor agonist peptide by a reaction with an enzyme, gastric acid, or the like under physiological conditions in vivo, i.e., a compound that is converted into a GIP receptor agonist peptide by an enzyme through oxidation, reduction, hydrolysis, or the like, or a polypeptide that is converted into a GIP receptor agonist peptide by hydrolysis with gastric acid, or the like.

[0296] Examples of prodrugs of GIP receptor agonist peptides include compounds in which the amino group of the GIP receptor agonist peptide is acylated, alkylated, or phosphorylated (e.g., compounds in which the amino group of the GIP receptor agonist peptide is eicosanoylated, alanylated, pentylaminocarbonylated, (5-methyl-2-oxo-1,3-dioxolen-4-yl)methoxycarbonylated, tetrahydrofuranylated, pyrrolidylmethylated, pivaloyloxymethylated, tert-butylated, or the like). a compound in which a hydroxy group of the GIP receptor agonist peptide is acylated, alkylated, phosphorylated, or boronated (e.g., a compound in which a hydroxy group of the GIP receptor agonist peptide is acetylated, palmitoylated, propanoylated, pivaloylated, succinylated, fumarylated, alanylated, or dimethylaminomethylcarbonylated); a compound in which a carboxy group of the GIP receptor agonist peptide is esterified or amidated (e.g., a compound in which a carboxy group of the GIP receptor agonist peptide is C 1-6 Examples of the esterified compounds include alkyl 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, and methylamidated compounds. In particular, the carboxy group of the GIP receptor agonist peptide may be substituted with a C methyl group such as methyl, ethyl, or tert-butyl. 1-6 Alkyl-esterified compounds are preferably used. These compounds, peptides and polypeptides can be prepared by methods known per se. , can be generated from GIP receptor agonist peptides.

[0297] The prodrug of the GIP receptor agonist peptide may also be converted into the GIP receptor agonist peptide under physiological conditions, as described in IYAKUHIN no KAIHATSU (Development of Pharmaceuticals), Vol. 7, Design of Molecules, pp. 163-198, Published by HIROKAWA SHOTEN (1990).

[0298] As used herein, prodrugs may form salts. Examples of such salts include those exemplified as salts of GIP receptor agonist peptides.

[0299] In some embodiments, the GIP receptor agonist peptide of the present disclosure can be synthesized and / or used as a crystal.Crystals having a single crystal form or a mixture of multiple crystal forms are also included in the GIP receptor agonist peptide example.Crystals can be produced by crystallizing the GIP receptor agonist peptide according to a known crystallization method.

[0300] Furthermore, the GIP receptor agonist peptide may be a pharmaceutically acceptable cocrystal or cocrystal salt. Here, a cocrystal or its salt refers to a crystalline substance consisting of two or more specific substances that are solid at room temperature and have different physical properties (e.g., structure, melting point, heat of fusion, hygroscopicity, stability, etc.). Cocrystals and cocrystal salts can be produced by cocrystallization, which is known per se.

[0301] The crystals of the GIP receptor agonist peptide of the present disclosure have excellent physicochemical properties (e.g., melting point, solubility, stability) and biological properties (e.g., pharmacokinetics (absorption, distribution, metabolism, excretion), onset of efficacy), and are therefore highly useful as pharmaceuticals.

[0302] In some embodiments, the GIP receptor agonist peptide and / or its prodrug (hereinafter sometimes abbreviated as the GIP receptor agonist peptide of the present disclosure) has a GIP receptor activating effect and may have selectivity as an agonist of the GIP receptor over other receptors such as GLP1R. The compound of the present disclosure has a highly selective GIP receptor activating effect in vivo.

[0303] C. Methods for preventing and treating GIP-mediated conditions, diseases, and disorders GIP is a gastrointestinal hormone called an incretin, which promotes insulin secretion from the pancreas. Because incretins are closely related to glucose metabolism, compounds with GIP receptor activating activity are useful for the prevention and treatment of conditions associated with abnormal glucose metabolism, such as diabetes and obesity. Furthermore, the compounds disclosed herein selectively activate GIP receptors and suppress vomiting by activating GABAergic neurons in the area postrema.

[0304] More specifically, the GIP receptor agonist peptide of the present disclosure has hypoglycemic and antiemetic effects.

[0305] The GIP receptor agonist peptides of the present disclosure have high chemical stability and excellent durability of effect in vivo.

[0306] The GIP receptor agonist peptides of the present disclosure can be used as GIP receptor activators.

[0307] In the present disclosure, a GIP receptor activator (GIP receptor agonist) refers to a drug having a GIP receptor activating action. Furthermore, a GIP receptor selective activator (GIP receptor peptide agonist) specifically has an EC 50 EC50 of the GIP receptor is 1 / 10 times or less, or 1 / 100 times or less, or 1 / 1000 times or less, preferably 1 / 10000 times or less. 50 means a drug having the formula:

[0308] The GIP receptor agonist peptides of the present disclosure have low toxicity (e.g., acute toxicity, chronic toxicity, genotoxicity, reproductive toxicity, cardiotoxicity, and carcinogenicity) and exhibit few side effects, and can be safely administered to mammals (e.g., humans, cows, horses, dogs, cats, monkeys, mice, and rats) as drugs for the prevention or treatment of various diseases such as those listed below.

[0309] Due to the above-mentioned activating effect on the GIP receptor, the GIP receptor agonist peptide of the present disclosure can be used as a drug for treating or preventing various diseases, including diabetes and obesity. The GIP receptor agonist peptide of the present disclosure can be used as a drug for the prevention or treatment of, for example, symptomatic obesity, obesity due to simple obesity, obesity-related conditions or diseases, eating disorders, diabetes (e.g., type 1 diabetes, type 2 diabetes, gestational diabetes, obesity-related diabetes), hyperlipidemia (e.g., hypertriglyceridemia, hypercholesterolemia, hyper-LDL cholesterolemia, hypo-HDL cholesterolemia, postprandial hyperlipidemia), hypertension, heart failure, diabetic complications (e.g., neuropathy, nephropathy, retinopathy, diabetic cardiomyopathy, cataracts, macroangiopathy, obesity, hyperosmolar diabetic coma, infections (e.g., respiratory infections, urinary tract infections, gastrointestinal infections, skin and soft tissue infections, lower limb infections), diabetic ganglion, xerostomia, hypoglycemia, cerebrovascular disease, peripheral blood circulatory disorders), metabolic syndrome (a condition consisting of three or more selected from hypertriglyceridemia (TG), hypo-HDL cholesterol (HDL-C), hypertension, abdominal obesity, and impaired glucose tolerance), sarcopenia, etc.

[0310] Examples of syndromic obesity include endocrine obesity (e.g., Cushing's syndrome, hypothyroidism, insulinoma, obese type II diabetes, pseudohypoparathyroidism, hypogonadism), central obesity (e.g., hypothalamic obesity, frontal lobe syndrome, Klein-Levin syndrome), genetic obesity (e.g., Prader-Willi syndrome, Laurence-Moon-Biedl syndrome), and drug-induced obesity (e.g., steroid-, phenothiazine-, insulin-, sulfonylurea-, and beta-blocker-induced obesity).

[0311] Examples of obesity-related conditions or diseases include impaired glucose tolerance, diabetes (particularly type 2 diabetes mellitus (T2DM) and obesity-related diabetes), dyslipidemia (synonymous with hyperlipidemia, as described above), hypertension, heart failure, hyperuricemia, fatty liver (including non-alcoholic steatohepatitis), coronary heart disease (myocardial infarction, angina pectoris), cerebral infarction (cerebral thrombosis, transient ischemic attack), bone / joint disease (knee osteoarthritis, hip osteoarthritis, spondylitis osteoarthritis, lower back pain), sleep apnea syndrome / Pickwickian syndrome, menstrual abnormalities (abnormal menstrual cycle, abnormal menstrual blood flow and cycle, amenorrhea, abnormal menstrual symptoms), metabolic syndrome, etc.

[0312] Regarding the diagnostic criteria for diabetes, new diagnostic criteria were reported by the Japan Diabetes Society in 1999.

[0313] According to this report, diabetes refers to a state in which a fasting blood glucose level (glucose concentration in venous plasma) of 126 mg / dl or more, a 2-hour value (glucose concentration in venous plasma) of 200 mg / dl or more in a 75 g oral glucose tolerance test (75 g OGTT), or a random blood glucose level (glucose concentration in venous plasma) of 200 mg / dl or more. In addition, a state that does not fall under the above-mentioned diabetes and does not show a "fasting blood glucose level (glucose concentration in venous plasma) of less than 110 mg / dl, or a 2-hour value (glucose concentration in venous plasma) of less than 140 mg / dl in a 75 g oral glucose tolerance test (75 g OGTT)" (normal type) is called "borderline type." It is called.

[0314] Furthermore, new diagnostic criteria for diabetes were reported by the American Diabetes Association (ADA) in 1997 and by the World Health Organization (WHO) in 1998.

[0315] According to these reports, diabetes refers to a condition in which a fasting blood glucose level (glucose concentration in venous plasma) is 126 mg / dl or higher and a 2-hour value (glucose concentration in venous plasma) of 200 mg / dl or higher in a 75 g oral glucose tolerance test.

[0316] According to the aforementioned report, impaired glucose tolerance refers to a state in which a fasting blood glucose level (glucose concentration in venous plasma) is less than 126 mg / dL and a 2-hour value (glucose concentration in venous plasma) of 140 mg / dL or more but less than 200 mg / dL in a 75g oral glucose tolerance test. According to the ADA report, a state in which a fasting blood glucose level (glucose concentration in venous plasma) is 110 mg / dL or more but less than 126 mg / dL is called IFG (impaired fasting glucose). On the other hand, according to the WHO report, a state in which a 2-hour value (glucose concentration in venous plasma) of less than 140 mg / dL in a 75g oral glucose tolerance test is called IFG (fasting hyperglycemia).

[0317] The GIP receptor agonist peptides of the present disclosure can also be used as drugs for the prevention or treatment of diabetes determined according to the above-mentioned new diagnostic criteria, borderline diabetes, impaired glucose tolerance, IFG (impaired fasting glucose), and IFG (hyperglycemia). Furthermore, the GIP receptor agonist peptides of the present disclosure can prevent the progression of borderline diabetes, impaired glucose tolerance, IFG (impaired fasting glucose), or IFG (hyperglycemia) to diabetes.

[0318] The GIP receptor agonist peptide of the present disclosure is also useful as a drug for preventing or treating metabolic syndrome.Compared with the patients with a single lifestyle-related disease, the incidence of cardiovascular disease is significantly higher in patients with metabolic syndrome.Therefore, the prevention or treatment of metabolic syndrome is very important for preventing cardiovascular disease.

[0319] The diagnostic criteria for metabolic syndrome were published by the WHO in 1999 and by the NCEP in 2001. According to the WHO diagnostic criteria, individuals who have the requirements of hyperinsulinemia or abnormal glucose tolerance and two or more of the following are diagnosed as having metabolic syndrome: visceral obesity, dyslipidemia (high TG or low HDL), and hypertension (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 Adult Treatment Panel III of the US National Cholesterol Education Program (Guidelines for Ischemic Heart Disease), individuals who have three or more of the following are diagnosed as having metabolic syndrome: visceral obesity, hypertriglyceridemia, low HDL cholesterol, hypertension, and abnormal glucose tolerance (National Cholesterol Education Program, Geneva, 1999). 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).

[0320] More specifically, the GIP receptor agonist peptides of the present disclosure have antiemetic effects and can inhibit or reduce the number and severity of nausea and / or vomiting episodes when associated with various stimuli disclosed herein, in patients suffering from cyclic vomiting syndrome or receiving potentially emetogenic chemotherapy drugs, such as platinum-based chemotherapy drugs such as cisplatin, oxaliplatin, and carboplatin, as well as irinotecan and other topoisomerase inhibitors used in the treatment of cancer. The GIP receptor agonist peptides of the present disclosure have high chemical stability and excellent durability of effect in vivo.

[0321] The GIP receptor agonist peptide of the present disclosure can be used as a GIP receptor activator. In the present disclosure, a GIP receptor activator (GIP receptor agonist) refers to a drug that has a GIP receptor activating action. Furthermore, a selective activator of the GIP receptor (i.e., as used herein, a GIP receptor agonist) specifically has an EC2 activity against the GLP-1 receptor. 50 EC50 of the GIP receptor is 1 / 1000-fold or less, preferably 1 / 10000-fold or less. 50 In other words, EC 50 GLP1R / EC 50 The GIPR ratio may be greater than 10, or greater than 100, or greater than 1,000, or greater than 10,000, or between about 100 and 1,000,000, or more.

[0322] The GIP receptor agonist peptides of the present disclosure have low toxicity (e.g., acute toxicity, chronic toxicity, genotoxicity, reproductive toxicity, cardiotoxicity, carcinogenicity), exhibit few side effects, and can be safely administered to mammals (e.g., humans, cows, horses, dogs, cats, monkeys, mice, rats) as agents for the prevention or treatment of emesis.

[0323] "Treatment," in the context of treating emesis by administering at least one of the GIP receptor agonist peptides disclosed herein, includes both preventative treatment and treatment of emesis after a subject has experienced emesis. Preventative treatment includes administration of the GIP receptor agonist peptide before the 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, drug, or event, or before the subject experiences or develops a condition that makes emesis likely. As used herein, a "therapeutically effective amount" refers to an amount of the GIP receptor agonist peptide sufficient to induce a desired biological response. In the present disclosure, the desired biological response is treatment and / or prevention of abnormal glucose metabolism in a subject in need thereof, including, for example, a subject with diabetes and obesity, or prevention and / or treatment of emesis in a subject in need thereof.

[0324] The GIP receptor agonist peptides of the present disclosure can be used to treat or prevent diabetes and / or obesity, pathophysiological conditions associated with diabetes and / or obesity, e.g., vomiting, when a subject is experiencing or about to experience vomiting, such as nausea and / or vomiting. In various embodiments, subjects, e.g., mammals, e.g., humans, non-human primates, apes, monkeys, laboratory mammals, e.g., mice, rats, rabbits, guinea pigs, ferrets, domestic animals such as companion mammals, e.g., dogs, cats, and horses, and livestock mammals, e.g., cows, pigs, sheep, and goats, can be treated with the GIP receptor agonist peptides of the present disclosure, purely by way of example, and not intended to be an exhaustive list. In each of these cases, the methods of the disclosure are provided for treating or preventing diabetes, obesity, or emesis, for reducing or inhibiting diabetes, obesity, or emesis, for reducing or inhibiting symptoms associated with diabetes, obesity, or emesis, or for reducing or inhibiting a condition or symptom associated with diabetes, obesity, or emesis, e.g., nausea and / or vomiting, in a subject in need thereof.

[0325] To prevent or treat vomiting, an effective amount of one or more compounds of the present invention in a pharmaceutical composition is administered to a subject / patient (used interchangeably herein) in need thereof.The subject is determined to be in need of treatment with the GIP receptor agonist peptide of the present invention either through the subject's observation of vomiting or through the subject's self-report of vomiting (in the case of a human subject).The patient is determined to be in need of prophylactic therapy by assessing that they are at risk of experiencing vomiting due to another medical condition, or due to viral or bacterial infection, or exposure to agents known to be associated with vomiting, such as chemicals or radiation.

[0326] The GIP receptor agonist peptides of the present invention are useful for treating 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 fluctuations in intracranial pressure. The use of the present invention is particularly useful in treating emesis induced by radiation, for example, during cancer or radiation sickness treatment, and in treating postoperative nausea and vomiting. Most particularly, the use of the present invention is useful in treating emesis induced by antineoplastic (cytotoxic) agents, including those routinely used in cancer chemotherapy, or by other agents, such as alpha-2 adrenergic receptor antagonists such as yohimbine, MK-912, and MK-467, and type IV cyclic nucleotide phosphodiesterase (PDE4) inhibitors such as RS14203, CT-2450, and rolipram.

[0327] Specific examples of chemotherapeutic agents are described, for example, by DJ Stewart in Nausea and Vomiting: Recent Research and Clinical Advances, ed. J. Kucharczyk et al., CRC Press Inc., Boca Raton, Fla., USA, 1991, pp. 177-203 (especially p. 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 chemicals, such as the toxins soman or sarin, or opioid drug use and / or withdrawal, such as morphine, heroin, oxycodone, etc., can also be prevented and / or treated.

[0328] The compound of the present invention is administered to a patient in an amount sufficient to treat or prevent the symptoms and / or underlying etiology associated with emesis in the patient. In a preferred embodiment, the GIP receptor agonist peptide is administered prior to the administration of a drug likely to cause emesis, such as one or more of the chemotherapeutic agents described above. The GIP receptor agonist peptide of the present invention can also be administered in combination with such a drug, either as a physical combination or in combination therapy by administering the compound of the present invention and the drug sequentially (in any order). Although the present invention is useful in any mammal suffering from emesis, the preferred subject is a human.

[0329] In some embodiments, the selective GIP agonists of the present disclosure can be administered to treat vomiting when a subject is concurrently treated for diabetes and / or obesity. Some known antidiabetic medications, such as metformin (Glucophage, Glumetza, etc.), ), sulfonylureas, meglitinides, thiazolidinediones, DPP-4 inhibitors, SGLT2 inhibitors, and GLP-1 receptor agonists are known to cause emesis. In some embodiments, a method for treating emesis in a subject, such as a method for treating in a subject in need thereof, can include administering an effective amount of a GIP receptor agonist peptide to a subject who does not have type 2 diabetes or who is not taking a medication to treat type 2 diabetes while experiencing vomiting.

[0330] Nausea is a subjective feeling of discomfort in the throat or back of the stomach that may lead to vomiting. Many terms are used to describe nausea, including, but not limited to, upset stomach, queasy, and upset stomach. Nausea can also cause other symptoms, such as increased saliva (saliva), dizziness, lightheadedness, difficulty swallowing, changes in skin temperature, and increased heart rate. Vomiting is also referred to as "puking up." When vomiting, the stomach muscles contract (squeeze), forcing the stomach contents out of the mouth. Nausea may or may not be felt. Retting is the attempt to vomit without expelling anything from the stomach. Other words used to describe nausea are gagging or dry heave. Nausea and vomiting often occur together, but they can be two different conditions that may be mutually exclusive or interrelated. Some chemotherapy drugs are more likely to cause nausea and vomiting than others. Doctors classify chemotherapy drugs as high, moderate, low, or minimal risk depending on their emetogenicity (how likely the drug is to cause nausea or vomiting).

[0331] The GIP receptor agonist peptides of the present disclosure can be used as prophylactic / therapeutic agents for vomiting and / or nausea caused by, for example, the clinical conditions or causes described in (1) to (10) below. Furthermore, the GIP receptor agonist peptides of the present disclosure can be used as prophylactic / therapeutic agents for chronic nausea and vomiting of unknown cause. Vomiting or nausea also includes unpleasant sensations such as nausea and vomiting, which are accompanied by an urgent desire to expel stomach contents through the mouth, and may also be accompanied by autonomic symptoms such as facial pallor, cold sweat, salivation, tachycardia, and diarrhea. Vomiting also includes acute vomiting, prolonged vomiting, and anticipatory vomiting. (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 due to infection, postoperative disease, myocardial infarction, migraine, intracranial hypertension, and intracranial hypotension (e.g., altitude sickness), (2)(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), metabolic inhibitors (e.g., cytarabine, methotrexate, 5-fluorouracil, enocitabine, and clofarabine), (ii) other chemotherapeutic agents such as vinca alkaloids (e.g., etoposide, vinblastine, and vincristine), cisplatin, procarbazine, hydroxyurea, azacitidine, irinotecan, interferon alpha, interleukin-2, oxaliplatin, carboplatin, nedaplatin, and miriplatin; (ii) opioid analgesics (e.g., morphine); (iii) dopamine receptor D1D2 agonists (e.g., apomorphine); (iv) vomiting and / or nausea induced by chemotherapeutic agents such as cannabis and cannabinoid products, including cannabis hypersensitivity syndrome; (3) Vomiting or nausea caused by radiation damage or radiation therapy to the chest, abdomen, etc. used to treat cancer (4) Vomiting or nausea caused by a toxic substance or toxin; (5) Vomiting and nausea caused by pregnancy, including hyperemesis gravidarum; (6) Vomiting and nausea caused by vestibular disorders such as motion sickness and dizziness, (7) opioid withdrawal; (8) Pregnancy, including hyperemesis gravidarum (9) Vestibular disorders such as motion sickness and dizziness (10) Physical injury causing localized, generalized, acute, or chronic pain.

[0332] These causes of vomiting, or nausea, or emesis are not intended to be exhaustive. Other conditions, activities, and side effects can cause vomiting, such as nausea and / or vomiting. Nausea can be measured by methods known in the art, such as using a visual analog scale (VAS).

[0333] The compounds of the present invention can also be used for secondary prevention or suppression of the progression of the above-mentioned various diseases (e.g., cardiovascular events such as myocardial infarction).The compounds of the present invention are also useful as food intake suppressants and weight loss agents.The compounds of the present invention can also be used in combination with dietary therapy (e.g., dietary therapy for diabetes) and exercise therapy.

[0334] D. Formulation Pharmaceuticals comprising the GIP receptor agonist peptides of the present disclosure have low toxicity and can be obtained by using the compounds of the present disclosure alone or in mixture with a pharmacologically acceptable carrier according to a method commonly used as a method for preparing pharmaceuticals and known per se (for example, a method described in the Japanese Pharmacopoeia), and can be safely administered orally or parenterally (for example, topically, rectally, or intravenously) in the form of pharmaceutical preparations, such as tablets (including sugar-coated tablets, film-coated tablets, sublingual tablets, and orally disintegrating tablets), powders, granules, capsules (including soft capsules and microcapsules), liquids, troches, syrups, emulsions, suspensions, injections (for example, subcutaneous injections, intravenous injections, intramuscular injections, intraperitoneal injections, etc.), external preparations (for example, nasal preparations, skin preparations, ointments), suppositories (for example, rectal suppositories, vaginal suppositories), pellets, nasal preparations, pulmonary preparations (inhalants), blood transfusions, etc.

[0335] These preparations may be controlled release preparations such as rapid release preparations or sustained release preparations (for example, sustained release microcapsules).The content of the compound of the present disclosure in the pharmaceutical preparation is about 0.01 to about 100% by weight of the total preparation.

[0336] The above-mentioned pharmaceutically acceptable carriers can be exemplified by various organic or inorganic carrier materials conventionally used as preparation materials, for example, excipients, lubricants, binders, and disintegrating agents for solid preparations, or solvents, solubilizers, suspending agents, isotonicity agents, buffers, soothing agents, etc. for liquid preparations. Furthermore, common additives such as preservatives, antioxidants, coloring agents, sweeteners, adsorbents, wetting agents, etc. can also be used appropriately in appropriate amounts, if necessary.

[0337] Examples of excipients include lactose, sucrose, D-mannitol, starch, corn starch, crystalline cellulose, and light anhydrous silicic acid.

[0338] Examples of lubricants include magnesium stearate, calcium stearate, colloidal talc, and the like.

[0339] Examples of binders include crystalline cellulose, sucrose, D-mannitol, dextrin, hydroxypropyl cellulose, hydroxypropylmethyl cellulose, polyvinylpyrrolidone, starch, sucrose, gelatin, methyl cellulose, sodium carboxymethyl cellulose, and the like.

[0340] Examples of disintegrants include starch, carboxymethylcellulose, Examples include calcium stearate, sodium carboxymethyl starch, and L-hydroxypropyl cellulose.

[0341] Examples of solvents include water for injection, alcohol, propylene glycol, macrogol, sesame oil, corn oil, olive oil, and the like.

[0342] Examples of solubilizers include polyethylene glycol, propylene glycol, D-mannitol, benzyl benzoate, ethanol, trisaminomethane, cholesterol, triethanolamine, sodium carbonate, and sodium citrate.

[0343] Examples of suspending agents include surfactants such as stearyl triethanolamine, sodium lauryl sulfate, lauryl aminopropionic acid, lecithin, benzalkonium chloride, benzethonium chloride, and glycerin monostearate; and hydrophilic polymers such as polyvinyl alcohol, polyvinylpyrrolidone, sodium carboxymethylcellulose, methylcellulose, hydroxymethylcellulose, hydroxyethylcellulose, and hydroxypropylcellulose.

[0344] Examples of isotonic agents include glucose, D-sorbitol, sodium chloride, glycerin, D-mannitol, and the like.

[0345] Examples of buffering agents include buffer solutions such as phosphate, acetate, carbonate, and citrate.

[0346] Examples of soothing agents include benzyl alcohol.

[0347] Examples of preservatives include parahydroxybenzoates, chlorobutanol, benzyl alcohol, phenethyl alcohol, dehydroacetic acid, and sorbic acid.

[0348] Examples of antioxidants include sulfites, ascorbic acid, α-tocopherol, and the like.

[0349] Examples of coloring agents include water-soluble food coal tar dyes (e.g., food colors such as Food Red Nos. 2 and 3, Food Yellow Nos. 4 and 5, and Food Blue Nos. 1 and 2), water-insoluble dye lakes (e.g., aluminum salts of the above-mentioned water-soluble food coal tar dyes), and natural dyes (e.g., β-carotene, chlorophyll, and ferric oxide red).

[0350] Examples of sweeteners include sodium saccharin, dipotassium glycyrrhizinate, aspartame, stevia, and the like.

[0351] Examples of adsorbents include porous starch, calcium silicate (trade name: Florite RE), magnesium aluminometasilicate (trade name: Neusilin), and light anhydrous silicic acid (trade name: Sylysia).

[0352] Examples of wetting agents include propylene glycol monostearate, sorbitan monooleate, diethylene glycol monolaurate, and polyoxyethylene lauryl ether.

[0353] During the manufacture of oral dosage forms, coatings can be applied as needed for taste masking, enteric properties, or durability purposes.

[0354] Examples of coating bases used for coating include sugar coating bases, aqueous film coating bases, enteric film coating bases, and sustained release film coating bases.

[0355] Sucrose is used as the sugar coating base, and one or more selected from talc, precipitated calcium carbonate, gelatin, gum arabic, pullulan, carnauba wax, etc. may be used in combination.

[0356] Examples of aqueous film coating bases include cellulose polymers such as hydroxypropyl cellulose, hydroxypropylmethyl cellulose, hydroxyethyl cellulose, and methylhydroxyethyl cellulose; synthetic polymers such as polyvinyl acetal diethylaminoacetate, aminoalkyl methacrylate copolymer E (Eudragit E (trade name)), and polyvinylpyrrolidone; and polysaccharides such as pullulan.

[0357] Examples of enteric film coating bases include cellulose polymers such as hydroxypropyl methylcellulose phthalate, hydroxypropyl methylcellulose acetate succinate, carboxymethylethylcellulose, and cellulose acetate phthalate; acrylic polymers such as methacrylic acid copolymer L [Eudragit L (trade name)], methacrylic acid copolymer LD [Eudragit L-30D55 ​​(trade name)], and methacrylic acid copolymer S [Eudragit S (trade name)]; and natural substances such as shellac.

[0358] Examples of sustained release film coating bases include cellulose polymers such as ethyl cellulose; acrylic polymers such as aminoalkyl methacrylate copolymer RS ​​(Eudragit RS®), ethyl acrylate-methyl methacrylate copolymer suspension (Eudragit NE®).

[0359] The above-mentioned coating bases can be used by mixing two or more types of coating bases in an appropriate ratio. For example, light-blocking agents such as titanium oxide and ferric oxide can be used in the coating.

[0360] E. Administration The therapeutically effective amount or dose of a composition or medicament containing a GIP receptor agonist peptide administered to a subject will depend on the age, sex, and weight of the patient, as well as the patient's current medical condition. Those skilled in the art will be able to determine the appropriate dosage depending on these and other factors to achieve the desired biological response.

[0361] The dosage of the GIP receptor agonist peptide of the present disclosure is appropriately determined depending on the subject, symptoms, administration method, etc. For example, when the GIP receptor agonist peptide of the present disclosure is orally administered to a subject before engaging in an activity likely to cause vomiting or after the onset of vomiting in a human subject (body weight approximately 60 kg), the daily dose of the compound of the present disclosure is about 0.01 to 100 mg, preferably about 1.0 to 50 mg, and more preferably about 1.0 to 20 mg. When the compound of the present disclosure is parenterally administered to an obese or diabetic patient or a patient with gastroparesis (body weight 60 kg), the daily dose of the compound of the present disclosure is about 0.001 to 30 mg, preferably about 0.01 to 20 mg, and more preferably about 0.1 to 10 mg. These amounts can be administered once or in divided doses per day. In some embodiments, the therapeutically effective amount of a GIP receptor agonist peptide for preventing and / or treating emesis in a subject in need thereof is about 0.01-0.5 mg / kg / day, 0.1-5 mg / kg / day, 5-10 mg / kg / day, 10-20 mg / kg / day, 20-50 mg / kg / day, 10-100 mg / kg / day, 10-120 mg / kg / day, It can be in the range of 50-100 mg / kg / day, 100-200 mg / kg / day, 200-300 mg / kg / day, 300-400 mg / kg / day, 400-500 mg / kg / day, 500-600 mg / kg / day, 600-700 mg / kg / day, 700-800 mg / kg / day, 800-900 mg / kg / day, or 900-1000 mg / kg / day.

[0362] The GIP receptor agonist peptides of the present disclosure can be administered, for example, every 2 days, every 3 days, every 4 days, every 5 days, every 6 days, weekly, twice a week, every other week, every 3 weeks, monthly, every 2 months, every 3 months, every 4 months, every 5 months, or every 6 months. In some embodiments, the GIP receptor agonist peptides of the present disclosure can be administered to a subject 1-3 times per day or 1-7 times per week for 1-5 days, 1-5 weeks, 1-5 months, or 1-5 years.

[0363] The GIP receptor agonist peptide of the present disclosure can be used in combination with another drug that does not adversely affect the GIP receptor agonist peptide of the present disclosure, for example, to enhance the action (analgesic effect) of the GIP receptor agonist peptide of the present disclosure, to reduce the dose of the GIP receptor agonist peptide of the present disclosure, etc.

[0364] Examples of drugs that can be used in combination with the GIP receptor agonist peptides of the present disclosure (hereinafter sometimes abbreviated as "concomitant drugs") include anti-obesity agents, therapeutic drugs for diabetes, therapeutic drugs for diabetic complications, therapeutic drugs for hyperlipidemia, antihypertensive drugs, diuretics, chemotherapy drugs, immunotherapeutic drugs, anti-inflammatory drugs, antithrombotic drugs, therapeutic drugs for osteoporosis, vitamins, anti-dementia drugs, drugs for erectile dysfunction, therapeutic drugs for urinary frequency or urinary incontinence, therapeutic drugs for dysuria, central D2 receptor antagonists, prokinetic agents, antihistamines, muscarinic receptor antagonists, serotonin 5HT3 receptor antagonists, somatostatin analogs, corticosteroids, benzodiazepine anxiolytics, NK-1 receptor antagonists, therapeutic drugs for hypercalcemia, etc. Specific examples of concomitant drugs include the following.

[0365] Examples of anti-obesity agents 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 modulators, GABA modulators (e.g., topiramate), neuropeptide Y antagonists (e.g., velneperit), cannabinoid receptor antagonists (e.g., rimonabant, taranabant), ), ghrelin antagonists, ghrelin receptor antagonists, ghrelin acylation enzyme inhibitors, opioid receptor antagonists (e.g., GSK-1521498), orexin receptor 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 DGAT1 inhibitors, acetyl-CoA carboxylase (ACC) inhibitors, stearoyl-CoA desaturase inhibitors, microsomal triglyceride transfer protein inhibitors (e.g., R-256918), Na-glucose cotransporter inhibitors (e.g., JNJ-28431754, remogliflozin), NFκ inhibitors (e.g., HE-3286), PPAR agonists (e.g., GFT-505, DRF-11605), phosphotyrosine phosphatase inhibitors (e.g., sodium vanadate, um, trodaschemin), 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, PYY3-36 derivatives, obinep TM-30339, TM-30335), oxyntomodulin preparations; FGF21 preparations (e.g., animal FGF21 preparations extracted from bovine or porcine pancreas; human FGF21 preparations genetically synthesized using Escherichia coli or yeast; FGF21 fragments or derivatives), appetite suppressants (e.g., P-57), GLP-1 receptor agonists, GLP-1 receptor / GIP receptor coagonists, glucagon receptor / GLP-1 receptor / GIP receptor triagonists, etc.

[0366] Here, examples of therapeutic agents for diabetes include insulin preparations (e.g., animal insulin preparations extracted from bovine or porcine pancreas, human insulin preparations genetically synthesized using Escherichia coli or yeast; zinc insulin; protamine zinc insulin; insulin fragments or derivatives (e.g., INS-1), oral insulin preparations), insulin sensitizers (e.g., pioglitazone or a salt thereof (preferably hydrochloride), rosiglitazone or a salt thereof (preferably maleate), metaglidasen, AMG-131, balaglitazone, MBX-2044, rivoglitazone, aleglitazar, tiglitazar, lobeglitazone, PLX-2044, , PN-2034, GFT-505, THR-0921, compounds 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 salts thereof (e.g., hydrochloride, fumarate, succinate)), insulin secretagogues (e.g., sulfonylureas (e.g., tolbutamide, gliben dipeptidyl peptidase IV inhibitors (e.g., alogliptin or a salt thereof (preferably benzoic acid), vildagliptin, sitagliptin, saxagliptin, BI1356, GRC8200, MP-513, PF-00734200, PHX1149, SK-0403, ALS2-04 26, TA-6666, TS-021, KRP-104, trelagliptin or a salt thereof (preferably succinic acid)), β3 agonists (e.g., N-5984), GPR40 agonists (e.g., fasiglifam or a hydrate thereof, compounds described in WO2004 / 041266, WO2004 / 106276, WO2005 / 063729, WO2005 / 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 its agonists, IKK inhibitors (e.g., AS-2868), leptin resistance improvers, somatostatin receptor agonists, glucokinase activators (e.g., piragliflozin, AZD1656, A Examples of suitable anti-inflammatory drugs include ZD6370, TTP-355, compounds described in WO006 / 112549, WO007 / 028135, WO008 / 047821, WO008 / 050821, WO008 / 136428, or WO008 / 156757), GPR119 agonists (e.g., PSN821, MBX-2982, APD597), FGF21, FGF analogs, ACC2 inhibitors, GLP-1 receptor agonists, GLP-1 receptor / GIP receptor co-agonists, glucagon receptor / GLP-1 receptor / GIP receptor triagonists, etc.

[0367] Examples of therapeutic agents for diabetic complications include aldose reductase inhibitors (e.g., trestat, epalstat, zopolrestat, fidarestat, CT-112, ranirestat (AS-3201), lidorestat), neurotrophic factors and their enhancers (e.g., NGF, NT-3, BDNF, neurotrophic factor production / min enhancers described in WO01 / 14372), and the like. secretagogues (e.g., 4-(4-chlorophenyl)-2-(2-methyl-1-imidazolyl)-5-[3-(2-methylphenoxy)propyl]oxazole, compounds described in WO2004 / 039365), PKC inhibitors (e.g., ruboxistaurin mesylate), AGE inhibitors (e.g., ALT946, N-phenacylthiazolium bromide (ALT766), EXO-226, pyridoline, pyridoxamine), GABA receptor agonists (e.g., gabapentin, pregabalin), serotonin and noradrenaline receptor agonists (e.g., steroids, antihistamines, anti-inflammatory drugs ... Examples of such an antihistamine include nalin reuptake inhibitors (e.g., duloxetine), sodium channel inhibitors (e.g., lacosamide), reactive oxygen scavengers (e.g., thioctic acid), cerebral vasodilators (e.g., tiapride, mexiletine), somatostatin receptor agonists (e.g., BIM23190), apoptosis signal-regulating kinase-1 (ASK-1) inhibitors, GLP-1 receptor agonists, GLP-1 receptor / GIP receptor co-agonists, and glucagon receptor / GLP-1 receptor / GIP receptor triagonists.

[0368] Examples of therapeutic agents for hyperlipidemia include HMG-CoA reductase inhibitors (e.g., pravastatin, simvastatin, lovastatin, atorvastatin, fluvastatin, rosuvastatin, pitavastatin, or a salt thereof (e.g., a sodium salt, a calcium salt)), squalene synthase inhibitors (e.g., compounds described in WO97 / 10224, such as 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]piperidine-4- acetate), fibrate compounds (e.g., bezafibrate, clofibrate, simfibrate, clinofibrate), anion exchange resins (e.g., cholestyramine), probucol, nicotinic acid drugs (e.g., nicomol, niceritrol, niaspan), ethyl isopentane, phytosterols (e.g., soy sterol, gamma oryzanol (γ-oryzanol)), cholesterol absorption inhibitors (e.g., Zekia), CETP inhibitors (e.g., dalcetrapib, anacetrapib), omega-3 fatty acid preparations (e.g., omega-3 fatty acid ethyl ester 90 (omega-3 acid ethyl ester 90)), and the like.

[0369] Examples of antihypertensive agents include angiotensin-converting enzyme inhibitors (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, carbedil, pindolol, etc.), clonidine, etc.

[0370] Examples of diuretics include xanthine derivatives (e.g., theobromine sodium salicylate, theobromine calcium salicylate, etc.), thiazide preparations (e.g., ethiazide, cyclopenthiazide, trichloromethiazide, hydrochlorothiazide, hydroflumethiazide, benzylhydrochlorothiazide, penfluthiazide, poly5thiazide, methylclothiazide, etc.), antialdosterone preparations (e.g., spironolactone, triamterene, etc.), carbonic anhydrase inhibitors (e.g., acetazolamide, etc.), chlorobenzenesulfonamides (e.g., chlorthalidone, mefruside, indapamide, etc.), azosemide, isosorbide, ethacrynic acid, piretanide, bumetanide, furosemide, etc.

[0371] Examples of chemotherapeutic agents include alkylating agents (e.g., cyclophosphamide, ifosfamide), antimetabolites (e.g., methotrexate, 5-fluorouracil), anticancer antibiotics (e.g., mitomycin, adriamycin), plant-derived anticancer agents (e.g., vincristine ... Examples of suitable anticancer drugs include cisplatin, carboplatin, etoposide, etc. 5-fluorouracil derivatives such as furtulon and N-neofurtulon are particularly preferred. Furthermore, compositions containing the GIP receptor agonist peptide of the present disclosure can be administered before, after, or during the administration of the following anticancer drugs: 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.

[0372] Examples of immunotherapies include microbial or bacterial components (e.g., muramyl dipeptide derivatives, picibanil), polysaccharides with immunopotentiating activity (e.g., lentinan, sizofiran, krestin), cytokines obtained by genetic engineering approaches (e.g., interferon, interleukin (IL)), and colony-stimulating factors (e.g., granulocyte colony-stimulating factor, erythropoietin). Interleukins such as IL-1, IL-2, and IL-12 are particularly preferred.

[0373] Examples of anti-inflammatory drugs include nonsteroidal anti-inflammatory drugs such as aspirin, acetaminophen, and indomethacin.

[0374] Examples of antithrombotic agents include heparin (e.g., heparin sodium, heparin calcium, enoxaparin sodium, dalteparin sodium), warfarin (e.g., warfarin potassium), antithrombin agents (e.g., aragatroban, dabigatran), FXa inhibitors (e.g., rivaroxaban, apixaban, edoxaban, YM150, WO02 / 06234, WO2004 / 048363, WO2005 / 030740, compounds described in 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 isopentate, beraprost sodium, sarpogrelate hydrochloride), and the like.

[0375] Examples of therapeutic agents for osteoporosis include alfacalcidol, calcitriol, elcatonin, calcitonin salmon, estriol, ipriflavone, pamidronate disodium, alendronate sodium hydrate, incadronate disodium, risedronate disodium, and the like.

[0376] Examples of vitamins include vitamin B1, vitamin B 12 etc.

[0377] Examples of anti-dementia drugs include tacrine, donepezil, rivastigmine, and galantamine.

[0378] Examples of erectile dysfunction drugs include apomorphine, sildenafil citrate, and the like.

[0379] Drugs for treating frequent urination or urinary incontinence include flavoxate hydrochloride, oxybutynin hydrochloride, propiverine hydrochloride, and the like.

[0380] Examples of therapeutic agents for dysuria include acetylcholinesterase inhibitors (eg, distigmine).

[0381] Examples of central D2 receptor antagonists include typical psychotropic drugs (prochlorperazine, haloperidol, chlorpromazine, etc.), serotonin dopamine antagonists (perospirone, risperidone, etc.), and multi-receptor-targeted antipsychotics (olanzapine, etc.).

[0382] Examples of prokinetic agents include peripheral D2 receptor antagonists (metoclopramide, domperidone, etc.) and 5HT4 receptor agonists (mosapride, etc.).

[0383] Examples of antihistamines include hydroxyzine, diphenhydramine, and chlorpheniramine.

[0384] Examples of muscarinic receptor antagonists include central muscarinic receptor antagonists (such as scopolamine) and peripheral muscarinic receptor antagonists (such as butylscopolamine).

[0385] Examples of serotonin 5HT3 receptor antagonists include granisetron, ondansetron, azasetron, indisetron, palonosetron, and ramosetron.

[0386] An example of a somatostatin analogue is octreotide.

[0387] Examples of corticosteroids include dexamethasone, betamethasone, and methylprednisolone.

[0388] Examples of benzodiazepine anxiolytics include lorazepam and alprazolam, examples of NK-1 receptor antagonists include aprepitant and fosaprepitant, and examples of antihypercalcemic drugs include bisphosphonates.

[0389] Additionally, drugs that have been confirmed to have cachexia-ameliorating effects either in animal models or clinically, i.e., cyclooxygenase inhibitors (e.g., indomethacin), progesterone derivatives (e.g., megestrol acetate), glucocorticoids (e.g., dexamethasone), metoclopramide drugs, tetrahydrocannabinol drugs, agents for improving fat metabolism (e.g., eicosapentaenoic acid), growth hormone, IGF-1, or antibodies against cachexia-inducing factors such as TNF-α, LIF, IL-6, or oncostatin M, may also be used in combination with the compounds of the present disclosure.

[0390] Alternatively, glycation inhibitors (e.g., ALT-711), neuroregeneration promoters (e.g., Y-128, VX853, prosaptide), antidepressants (e.g., desipramine, amitriptyline, imipramine), antiepileptic drugs (e.g., lamotrigine, trileptal, keppra, zonegran, pregabalin, halcoceride, carbamazepine), antiarrhythmic drugs (e.g., mexiletine), acetylcholine receptor ligands (e.g., ABT-594), endothelin receptor antagonists (e.g., ABT-627), monoamine agonists (e.g., thiazolinone, thiazolinone, thiazolinone, thiazolinone), thiazolinone, ... Antihistamines, antihistamines, anti-inflammatory drugs ...

[0391] The administration time of the GIP receptor agonist peptide of the present disclosure and the administration time of the concomitant drug are limited. They can be administered to a subject simultaneously or at staggered times.

[0392] Examples of such administration methods include the following: (1) Administration of a single formulation obtained by simultaneous treatment of the GIP receptor agonist peptide of the present disclosure and the concomitant drug; (2) Simultaneous administration of two types of formulations, the GIP receptor agonist peptide of the present disclosure and the concomitant drug, which have been manufactured separately, by the same administration route; (3) staggered administration of two types of formulations, the GIP receptor agonist peptide of the present disclosure and the concomitant drug, which have been manufactured separately, by the same administration route; (4) Simultaneous administration of two types of formulations, the GIP receptor agonist peptide of the present disclosure and the concomitant drug, which have been manufactured separately, by different administration routes; (5) staggered administration of two types of formulations, the GIP receptor agonist peptide of the present disclosure and the concomitant drug, which have been manufactured separately, by different administration routes (e.g., administration of the GIP receptor agonist peptide of the present disclosure and the concomitant drug in the order, or administration in the reverse order), etc.

[0393] The dose of the concomitant drug can be appropriately determined based on the dosage used in clinical situations. The mixing ratio of the GIP receptor agonist peptide of the present disclosure to the concomitant drug can be appropriately determined depending on the administration subject, symptoms, administration method, target disease, combination, etc. For example, when the administration subject is a human, the concomitant drug can be used in an amount of 0.01 to 100 parts by weight per part by weight of the GIP receptor agonist peptide of the present disclosure.

[0394] By combining the GIP receptor agonist peptide of the present disclosure with a concomitant drug, (1) the dose of the GIP receptor agonist peptide of the present disclosure or the concomitant drug can be reduced compared to a single administration of the GIP receptor agonist peptide of the present disclosure or the concomitant drug, (2) The drug to be used in combination with the GIP receptor agonist peptide of the present disclosure can be selected depending on the patient's condition (mild, severe, etc.), (3) By selecting a concomitant drug having an action and mechanism different from that of the GIP receptor agonist peptide of the present disclosure, the treatment period can be set longer, (4) A sustained therapeutic effect can be designed by selecting a concomitant drug having an action and mechanism different from the GIP receptor agonist peptide of the present disclosure; (5) By using the GIP receptor agonist peptide of the present disclosure in combination with a concomitant drug, etc., a synergistic effect can be achieved. [Example]

[0395] F. Working Example The abbreviations used herein have the following meanings (Table 1). Hyphens such as α-MePhe described herein may be omitted, and even if omitted, the meaning remains the same.

[0396] As used herein, in amino acid sequences, the left end represents the N-terminus and the right end represents the C-terminus.

[0397] [Table 1] JPEG2026009897000005.jpg241145JPEG2026009897000006.jpg225147 [ka] PEG linker used for Cys. PEG = 5-30kDa PEG [ka]

[0398] In the present specification, bases, amino acids, etc. are represented by codes based on conventional codes in accordance with the IUPAC-IUB Biochemical Nomenclature Commission or codes commonly used in the art, examples of which are shown below. For amino acids that may have optical isomers, the L-form is shown unless otherwise specified (e.g., "Ala" is the L-form of Ala). Furthermore, "D-" means the D-form (e.g., "D-Ala" is the D-form of Ala), and "DL-" means a racemate of the D-form and the L-form (e.g., "DL-Ala" is the DL-racemate of Ala).

[0399] The present disclosure will be described in detail below with reference to reference examples, examples, test examples, and formulation examples, but these are merely embodiments and should not be construed as limiting. Furthermore, the present disclosure can be modified without departing from the scope of the present invention.

[0400] In the following examples, "room temperature" generally refers to a range of about 10° C. to about 35° C. Regarding "%," yields are in mole / mole %, solvents used for chromatography are in volume %, and other "%" are in weight %. 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: 2-cyano-2-(hydroxyimino)acetic acid ethyl ester

[0401] Example 1. Synthesis scheme Exemplary methods for synthesizing GIP receptor agonist peptides are disclosed, for example, on pages 162-213 of Applicant's International PCT Application No. PCT / JP2018 / 013540, filed March 30, 2018, the disclosure of which is specifically incorporated herein by reference in its entirety.

[0402] Synthesis of exemplary GIP receptor agonist peptides of the present disclosure Example 2. Exemplary Synthesis of Exemplary Selective GIP Receptor Agonist Peptides of the Disclosure Synthesis. Compound No. 7, SEQ ID NO: 18 Step 1 Boc-Tyr(tBu)-Aib-Glu(OtBu)-Gly-Thr(tBu)-Val-Val-Ser(tBu)-Leu-Tyr(tBu)-Ser(tBu)-Ile-Aib-Leu-Asp(OtBu)-Lys(boc)-Gln(Trt)-Ala-Gln(Trt)-Aib-Gl Synthesis of u(OtBu)-Phe-Val-Lys(Boc)-Trp(Boc)-Leu-Leu-Lys(Boc)-Gly-Gly-Pro-Ser(tBu)-Ser(tBu)-Gly-Ala-Pro-Pro-Pro-Ser(tBu)-Lys-Sieber amide resin (compound 7-intermediate) Sieber amide resin (0.71 meq / g, 140.8 mg, 0.1 mmol) was added to a reaction tube and loaded into an automated microwave peptide synthesizer (CEM Liberty Blue). The amino acids were sequentially elongated according to the protocol using 20% ​​piperidine / DMP (reaction at 90 °C for 1 min) for Fmoc deprotection and 5 equivalents of Fmoc-amino acid / DIPCDI / oxymer (reaction at 90 °C for 2 min) for Fmoc-amino acid condensation. Condensations at Ile at position 12, Leu at position 9, Val at position 6, and Thr(tBu) at position 5 were carried out by a double coupling method. After the condensation was completed, the resin was washed with MeOH and dried under reduced pressure to give Boc-Tyr(tBu)-Aib-Glu(OtBu)-Gly-Thr(tBu)-Val-Val-Ser(tBu)-Leu-Tyr(tBu)-Ser(tBu)-Ile-Aib-Leu-Asp(OtBu)-Lys(boc)-Gln(Trt)-Ala-Gln(Trt)-Aib-Glu(OtBu)-Phe-Val-Lys(Boc)-Trp(Boc)-Leu-Leu-Lys(Boc)-Gly-Gly-Pro-Ser(tBu)-Ser(tBu)-Gly-Ala-Pro-Pro-Pro-Ser(tBu)-Lys(Alloc)-Sieber amide resin. To the dried resin was added tetrakis(triphenylphosphine)palladium(0) (288.9 mg, 0.25 mmol) in 4.0 mL of toluene:AcOH:4-methylmorpholine (37:2:1). The mixture was shaken at room temperature under Ar for 16 hours (overnight). The reaction solution was filtered. The resin was then washed with toluene, 0.5 wt% sodium N,N-diethyldithiocarbamate trihydrate / NMP, DIEA / NMP, NMP, and MeOH, and dried under reduced pressure. This resulted in 470.1 mg (0.213 meq / g) of the desired protected peptide resin.

[0403] Step 2 Tyr-Aib-Glu-Gly-Thr-Val-Val-Ser-Leu-Tyr-Ser-Ile-Aib-Leu-Asp-Lys-Gln-Ala-Gln-Aib-Glu-Phe-Val-Lys-Trp -Synthesis of -Leu-Leu-Lys-Gly-Gly-Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser-Lys(Heda-Gly-Gly-Gly-Gly-) (SEQ ID NO: 18) (Compound 7) Boc-Tyr(tBu)-Aib-Glu(OtBu)-Gly-Thr(tBu)-Val-Val-Ser(tBu)-Leu-Tyr(tBu)-Ser(tBu)-Ile-Aib-Leu-Asp(OtBu)-Lys(boc)-Gln(Trt)-Ala-Gln(Trt)-Aib-Glu(OtBu)-Phe-Val-Lys(Boc)-Trp(Boc)-Leu-Leu-Lys(Boc)-Gly-Gly-Pro-Ser(tBu)-Ser(tBu)-Gly-Ala-Pro-Pro-Pro-Ser(tBu)-Lys-Sieber amide resin (SEQ ID NO:XXX) (40.6 mg, 0.01 mmol) synthesized in step 1 was weighed into a reaction tube and swollen with NMP. After removing the NMP by filtration, Fmoc-Gly-OH (14.9 mg), 0.5 M oxymer in NMP (100 μL), and diisopropylcarbodiimide (8.0 μL) were added successively to the resin, and the mixture was then shaken overnight. After filtering the reaction solution, the resin was washed 10 times with NMP. Then, Fmoc-Gly-OH (14.9 mg), 0.5 M oxymer in NMP (100 μL), and diisopropylcarbodiimide (8.0 μL) were added again. The mixture was shaken for 4.5 hours.

[0404] After confirming a negative ninhydrin test, a 20% NMP solution of piperidine was added thereto, and the mixture was shaken for 1 minute. The solution was filtered, and then a 20% NMP solution of piperidine was added thereto again, and the mixture was shaken for 20 minutes. After filtering the solution, the resin was washed with NMP 10 times. This Fmoc amino acid condensation (double coupling)-Fmoc deprotection cycle was repeated to obtain Gly, Gly, Gly*, and Heda(OtBu).** were successively condensed ( * : Overnight single coupling, ** The resin was washed with MeOH and dried under vacuum to give 41.4 mg of the desired protected peptide resin, Boc-Tyr(tBu)-Aib-Glu(OtBu)-Gly-Thr(tBu)-Val-Val-Ser(tBu)-Leu-Tyr(tBu)-Ser(tBu)-Ile-Aib-Leu-Asp(OtBu)-Lys(Boc)-Gln(Trt)-Ala-Gln. (Trt)-Aib-Glu(OtBu)-Phe-Val-Lys(Boc)-Trp(Boc)-Leu-Leu-Lys(Boc)-Gly-Gly-Pro-Ser(tBu)-Ser(tBu)-Gly-Ala-Pro-Pro-Pro-Ser(tBu)-Lys(Heda(OtBu)-Gly-Gly-Gly-Gly-)-Sieber amide resin was obtained. To the total amount of resin obtained, 0.5 mL of TFA:m-cresol:thioanisole:ethanedithiol:HO:triisopropylsilane (80:5:5:5:2.5:2.5) was added, and the resulting mixture was stirred for 1.5 hours. Diethyl ether was added to the reaction solution to obtain a precipitate. After centrifugation, the supernatant was removed. Diethyl ether was added to the precipitate, and after centrifugation, the supernatant was removed. This procedure was repeated twice. The residue was extracted with 50% aqueous acetic acid, and the resin was removed by filtration. The product was purified by preparative HPLC using a Phenomenex Kinetex XB-C18 100A column (250 × 21.1 mm ID) with a linear gradient elution (A / B: 63 / 37 to 53 / 47) at a flow rate of 8 mL / min (60 min) using Solution A: 0.1% TFA-water and Solution B: 0.1% TFA-acetonitrile. The fractions containing the desired product were collected and lyophilized to obtain 1.0 mg of a white powder.

[0405] Mass spectrometry: (M+H)+ 4727.46 (calculated 4727.57) HPLC elution time: 15.23 min Elution conditions: Column: Kinetex XB-C18 100A (4.6 x 100 mm ID) Elution solution: Solution A: 0.1% TFA-water, Solution B: 0.1% TFA-containing acetonitrile, A / B: 80 / 20 to 30 / 70. Linear gradient elution (25 min). Flow rate: 1.0mL / min Temperature: room temperature

[0406] Example 2: Synthesis of exemplary GIP receptor agonist peptides of the present disclosure. Synthesis of Compound 60; SEQ ID NO: 71 Step 1 Boc-MeTyr(tBu)-Aib-Glu(OtBu)-Gly-Thr(tBu)-Phe-Ile-Ser(tBu)-Asp(OtBu)-Tyr(tBu)-Ser(tBu)-Ile-Ala-Leu-Asp(OtBu)-Arg(Pbf)-Aib-His(Trt)-Gln(Trt)-Aib- Synthesis of Asn(Trt)-Phe-Val-Asn(Trt)-Trp(Boc)-Iva-Leu-Ala-Gln(Trt)-Arg(Pbf)-Pro-Ser(tBu)-Ser(tBu)-Gly-Ala-Pro-Pro-Pro-Ser(tBu)-Lys-Sieber amide resin (compound 7-intermediate) Sieber amide resin (0.71 meq / g, 70.4 mg, 0.05 mmol) was added to the reaction tube and loaded into the peptide synthesizer. 20% HCl was added to the reaction tube to deprotect the Fmoc group. The amino acids were sequentially elongated according to a protocol using piperidine / NMP (reaction time: 5 min at 50°C) and 5 equivalents of Fmoc-amino acid / DIPCDI / oxymer (reaction time: 15 min at 50°C) for condensation of Fmoc-amino acid. In this case, the condensation reactions of Boc-MeTyr(tBu) at position 1, Thr(tBu) at position 5, Ile at position 12, Arg(Pbf) at position 16, Gln(Trt) at position 19, Trp(Boc) at position 25, Leu at position 27, and Lys(ivDde) ​​at position 40 were carried out at 50°C for 30 min.

[0407] The obtained Boc-MeTyr(tBu)-Aib-Glu(OtBu)-Gly-Thr(tBu)-Phe-Ile-Ser(tBu)-Asp(OtBu)-Tyr(tBu)-Ser (tBu)-Ile-Ala-Leu-Asp(OtBu)-Arg(Pbf)-Aib-His(Trt)-Gln(Trt)-Aib-Asn(Trt)-Phe-Val-Asn(T rt)-Trp(Boc)-Iva-Leu-Ala-Gln(Trt)-Arg(Pbf)-Pro-Ser(tBu)-Ser(tBu)-Gly-Ala-Pro-Pro-Pro-Ser(tBu)-Lys(ivDde)-Sieber amide resin was suspended in 2% hydrazine / NMP solution, the resulting suspension was stirred at 50°C for 10 minutes, and the solution was then removed by filtration.

[0408] This procedure was repeated four times to deprotect the ivDde group of Lys at position 40.

[0409] The resulting resin was washed with MeOH and dried under reduced pressure to give 373.4 mg of Boc-MeTyr(tBu)-Aib-Glu(OtBu)-Gly-Thr(tBu)-Phe-Ile-Ser(tBu)-Asp(OtBu)-Tyr(tBu)-Ser(tBu)-Ile-Ala-Leu-Asp(OtBu)-Arg(Pbf)-Aib-His(Trt)-Gln(Trt)-Aib-Asn(Trt)-Phe-Val-Asn(Trt)-Trp(Boc)-Iva-Leu-Ala-Gln(Trt)-Arg(Pbf)-Pro-Ser(tBu)-Ser(tBu)-Gly-Ala-Pro-Pro-Pro-Ser(tBu)-Lys-Sieber amide resin.

[0410] Step 2 Boc-MeTyr(tBu)-Aib-Glu(OtBu)-Gly-Thr(tBu)-Phe-Ile-Ser(tBu)-Asp(OtBu)-Tyr(tB u)-Ser(tBu)-Ile-Ala-Leu-Asp(OtBu)-Arg(Pbf)-Aib-His(Trt)-Gln(Trt)-Aib-Asn(Trt )-Phe-Val-Asn(Trt)-Trp(Boc)-Iva-Leu-Ala-Gln(Trt)-Arg(Pbf)-Pro-Ser(tBu)-Ser(tBu)-Gly-Ala-Pro-Pro-Pro-Ser(tBu)-Lys(Oda-GlyGlyGlyGlyGlyGly) (SEQ ID NO: 71) (Compound 60). Step 1 synthesized Boc-MeTyr(tBu)-Aib-Glu(OtBu)-Gly-Thr(tBu)-Phe-Ile-Ser(tBu)-Asp(OtBu)-Tyr(tBu)-Ser(tBu)-Ile-Ala-Leu-Asp(OtBu)-Arg(Pbf)-Aib-His(Trt)-Gln(Trt)-Aib-Asn(Trt)-Phe-Val-Asn(Trt)-Trp(Boc)-Iva-Leu-Ala-Gln(Trt)-Arg(Pbf)-Pro- Ser(tBu)-Ser(tBu)-Gly-Ala-Pro-Pro-Pro-Ser(tBu)-Lys-Sieber amide resin (74 mg, 0.01 mmol) was weighed into a reaction tube and loaded into a peptide synthesizer. The amino acids were sequentially elongated according to the protocol using 20% ​​piperidine / NMP (5 min at 50 °C) for deprotection of the Fmoc group and 5 equivalents of Fmoc-amino acid / DIPCDI / oxymer (15 min at 50 °C) for condensation of the Fmoc-amino acid. The coupling reaction was repeated twice to introduce Fmoc-GlyGlyGly-OH, Fmoc-GlyGly-OH, and Fmoc-Gly-OtBu. For Oda, the reaction was carried out for 30 minutes.

[0411] The resulting resin was washed with MeOH and dried under reduced pressure to give 79.4 mg of the desired protected peptide resin, Boc-MeTyr(tBu)-Aib-Glu(OtBu)-Gly-Thr(tBu)-Phe-Ile-Ser(tBu)-Asp(OtBu)-Tyr(tBu)-Ser(tBu)-Ile-Ala-Leu-Asp(OtBu)-Arg(Pbf)-Aib-Hi s(Trt)-Gln(Trt)-Aib-Asn(Trt)-Phe-Val-Asn(Trt)-Trp(Boc)-Iva-Leu-Ala-Gln(Trt)-Arg(Pbf)-Pro-Ser(tBu)-Ser(tBu)-Gly-Ala-Pro-Pro-Pro-Ser(tBu)-Lys(Oda-GlyGlyGlyGlyGly)-Sieber amide resin was obtained.

[0412] To the total amount of resin obtained, 0.8 mL of TFA:m-cresol:thioanisole:ethanedithiol:HO:triisopropylsilane (80:5:5:5:2.5:2.5) was added, and the resulting mixture was stirred for 1.5 h. Diethyl ether was added to the reaction solution to obtain a precipitate, and after centrifugation, the supernatant was removed. Diethyl ether was added to the precipitate, and after centrifugation, the supernatant was removed. This procedure was repeated twice. The residue was extracted with 90% aqueous acetic acid, and the resin was removed by filtration. The product was purified by preparative HPLC using a YMC-Actus Triart C8 (250 x 20 mm ID) column with a linear gradient elution (A / B: 59 / 41 to 49 / 51) at a flow rate of 8 mL / min. The fractions containing the desired product were collected and lyophilized to obtain 8.2 mg of a white powder. Mass spectrometry result: (M+H)+ 5127.07 (calculated 5126.64) HPLC elution time: 5.62 min Elution conditions: Column: Kinetex 1.7 μm C8100A (100 × 2.1 mm ID) Elution solution: Solution A: 0.1% TFA-water, Solution B: 0.1% TFA-containing acetonitrile, A / B: 80 / 20 to 30 / 70. Linear gradient elution (10 min). Flow rate: 0.5mL / min Temperature: 40 degrees

[0413] The powder was dissolved in 50% acetonitrile-water, and 20 μL of ion-exchange resin (AG 1×8 resin (acetate form), 1.2 meq / mL) was added to the solution. The mixture was shaken for 1 hour. After removing the resin by filtration, the filtrate was lyophilized to obtain 6.9 mg of the desired acetate product. Mass spectrometry results: (M+H) + 5128.06 (calculated value 5126.64) HPLC elution time: 5.58 min Elution conditions: Column: Kinetex 1.7 μm C8100A (100 × 2.1 mm ID) Elution solution: Solution A: 0.1% TFA-water, Solution B: 0.1% TFA-containing acetonitrile, A / B: 80 / 20 to 30 / 70. Linear gradient elution (10 min). Flow rate: 0.5mL / min Temperature: 40℃

[0414] [Table 2] JPEG2026009897000010.jpg235156JPEG2026009897000011.jpg239155JPEG2026009897000012.jpg92169

[0415] Example 3. Additional Peptide Synthesis Methods: The peptides were synthesized using standard Fmoc chemistry. (1) To 1-chloro-2-[chloro(diphenyl)methyl]benzene (0.1 mmol, 1.0 equiv.) was added FMOC-SER(TBU)-OH (115 mg, 300 µmol, 3.0 equiv.) and DIEA (77.5 mg, 600 µmol, 104 µL, 6.0 equiv.) in DCM (5 mL). The mixture was stirred with N2 at 20 °C for 2 h, then MeOH (0.2 mL) was added and stirred with N2 for an additional 30 min. The mixture was drained and washed three times with DMF for 30 s. (2) Add 20% piperidine / DMF and mix for 30 minutes. (3) Drain and wash with DMF five times for 30 seconds. (4) Add the Fmoc-amino acid solution and mix for 30 seconds, then add the activation buffer and aerate with N2 for about 1 hour. Add 20% piperidine / DMF and react for 30 minutes. (5) Repeat steps 2 to 5 for the next amino acid coupling.

[0416] [Table 3] JPEG2026009897000014.jpg103169

[0417] 20% piperidine in DMF was used for 30 min for Fmoc deprotection. 3% NH2NH2 in DMF was used twice for 20 min for Dde deprotection. The coupling reaction was monitored by the ninhydrin test, and the resin was washed five times with DMF.

[0418] Peptide cleavage and purification: (1) Add cleavage buffer (90% TFA / 2.5% EDT / 2.5% TIS / 2.5% HO / 2.5% methylsulfanylbenzene) to the flask containing the side-chain protected peptide and stir for 3 hours. (2) The filtrate is collected by filtration, and the peptide is precipitated with cold tert-butyl methyl ether and centrifuged (3000 rpm for 3 minutes). (3) The tert-butyl methyl ether is washed two more times. (4) The crude peptide is dried under vacuum for 2 hours. (5) Purify the crude peptide by preparative HPLC (A: 0.075% TFA in HO, B: ACN) followed by preparative HPLC (HOAc conditions; A: 0.5% HOAc in HO, B: ACN) to obtain the final product (17 mg, 3.37 μmol, 3.3% yield, 99.2% purity, HOAC).

[0419] [Table 4] [Table 5] [Table 6] JPEG2026009897000018.jpg239155JPEG2026009897000019.jpg236155JPEG2026009897000020.jpg235153JPEG2026009897000021.jpg80170 [Table 7] JPEG2026009897000023.jpg185166

[0420] Biological Examples Methods for conducting GIP and GLP receptor binding assays, assays for inhibition of emesis, vomiting, and nausea caused by various stimuli, including drug- or chemotherapy-induced emesis, are specifically described on pages 213 to 255 of Applicant's International PCT Application No. PCT / JP2018 / 013540, filed March 30, 2018, and are specifically incorporated herein by reference in their entirety.

[0421] Example 1. Evaluation of agonist activity against human GIPR and human GLP-1R using an increase in intracellular cAMP concentration as an index A) Increase in intracellular cAMP concentration was used as an indicator for the activity of human GIPR and human GLP-1R. Evaluation of agonist activity (1) Construction of an expression plasmid for the human GIPR gene. The human GIPR gene having the same sequence as that of Genebank accession number U39231 was cloned into the pMSRα-neo vector to prepare hGIPR / pMSRα-neo.

[0422] (2) A reporter plasmid expressing a luciferase reporter gene containing a cAMP response element upstream of the gene was introduced into CHO-K1 cells to construct CRE-LUC / CHO-K1 cells.

[0423] (3) Construction of reporter plasmid The cAMP response element and four copies of the Zeocin resistance gene were transferred into the pGL3(R2.2)-Basic vector (Promega) to construct the Cre-luc(Zeo) reporter plasmid.

[0424] (4) Introduction of the human GIPR gene into CRE-LUC / CHO-K1 cells and isolation of expressing cells The plasmid hGIPR / pMSRα-neo obtained in (1) was transferred to CRELUC.

[0425] To obtain transformants, the CHO-K1 cells obtained in (2) were used. Next, from the resulting transformants, a cell line, hGIPR / CRE-LUC / CHO-K1 cells, in which luciferase expression was induced by the addition of GIP was selected.

[0426] (5) Construction of an expression plasmid for the human GLP-1R gene The human GLP-1R gene having the same sequence as Genebank accession number NM_002062 was cloned into the pIRESneo3 vector to prepare hGLP-1 / pIRESneo3.

[0427] (6) Human GLP-1R gene and reporter plasmid were introduced into CHO-K1 cells to obtain expressing cells. The Cre-luc(Zeo) plasmid obtained in (3) and the hGLP-1 / pIRESneo3 plasmid obtained in (5) were introduced into CHO-K1 cells to obtain transformants. From the resulting transformants, a cell line, hGLP-1R / CRE-luc / CHO-K1 cells, in which luciferase expression was induced by the addition of GLP-1 was selected.

[0428] (7) Reporter assay 25 μL of hGIPR / CRE-LUC / CHO-K1 cells were plated in a 384-well white plate (Corning) at 5 × 10 3 Cells were seeded at a concentration of 0.1% per well and cultured overnight at 37°C in a CO2 incubator in HamF12 medium containing 10% fetal bovine serum, 100 U / mL penicillin, and 100 μg / mL streptomycin. Five μL of medium containing test compounds was added to the cells and incubated for 4 hours at the indicated concentrations in a CO2 incubator at 37°C. Steady-Glo (Promega) was added in a volume of 30 μL, and the cells were shaken in the dark. After 20 minutes, luciferase activity was measured using a plate reader Envision (PerkinElmer). GIPR agonist activity was calculated using the increase in intracellular cAMP concentration as an indicator, where luciferase activity in the presence of 10 nM GIP was 100% and luciferase activity when DMSO was added instead of the test compound was 0%.

[0429] GLP-1R agonist activity was assayed using hGLP-1R / CRE-luc / CHO-K1 cells in the same manner as described above. GLP-1R agonist activity was measured by intracellular cA The increase in MP concentration was calculated as a sample, with luciferase activity in the presence of 10 nM GLP-1 being 100% and luciferase activity when DMSO was added instead of the test compound being 0%.

[0430] As shown in Table 8, the GIP receptor agonist peptides of the present disclosure have excellent selective GIP receptor activation activity.

[0431] [Table 8] JPEG2026009897000025.jpg239149JPEG2026009897000026.jpg236149JPEG2026009897000027.jpg64163

[0432] Example 4 - Evaluation of peptide agonist activity on human GIPR and human GLP1R by measuring intracellular cAMP accumulation (HDB protocol) GIPR assay HEK-293T cells overexpressing full-length human GIPR with an N-terminal FLAG tag and a sequence identical to GenBank accession number NM_000164 are purchased from Multispan, Inc. (Hayward, CA). Cells are cultured in DMEM containing 10% fetal bovine serum and 1 μg / mL puromycin according to the manufacturer's protocol and stored in frozen aliquots for use as assay-ready cells. On the day of the assay, cells are removed from frozen storage, washed twice with 1x Krebs-Ringer buffer (Zenbio, Research Triangle Park, NC), and cultured at 4 x 10 in 1x Krebs-Ringer buffer. 5 Resuspend to a concentration of 3 x 10 cells / mL. -10 ~5.08×10 -15 50 nL of test compound in 100% DMSO spanning a final concentration range of 10 M was acoustically dispensed in small volumes into a white 384-well polypropylene plate (Corning, Tewksbury, MA) and placed at 4 × 10 per well in a total volume of 10 μL. 3Cells are added. Cells are incubated with test compounds in the dark for 1 hour at room temperature, and cAMP accumulation is measured using a Cisbio HiRange cAMP Assay Kit (Bedford, MA) according to the manufacturer's protocol. Anti-cAMP antibody and d2-cAMP tracer reagent diluted in lysis / detection buffer are incubated in the dark for 1 hour, and the results are measured using an Envision plate reader (Perkin Elmer, Waltham, MA). Data are normalized using 1 nM GIP as 100% activity and DMSO alone as 0% activity.

[0433] Example 5 - GLP1R Assay HEK-293T cells overexpressing full-length human GLP-1R with an N-terminal FLAG tag and a sequence identical to GenBank accession number NM_002062 can be purchased from Multispan, Inc. (Hayward, CA). Cells are cultured in DMEM containing 10% fetal bovine serum and 1 μg / mL puromycin according to the manufacturer's protocol and stored in frozen aliquots for use as assay-ready cells. On the day of the assay, cells are removed from frozen storage, washed twice with 1x Krebs-Ringer buffer (Zenbio, Research Triangle Park, NC), and cultured at 4 x 10 in 1x Krebs-Ringer buffer. 5 Resuspend to a concentration of 1 x 10 cells / mL. -6 ~1.69×10 -11 50 nL of test compound in 100% DMSO spanning a final concentration range of 10 M was acoustically dispensed in small volumes into a white 384-well polypropylene plate (Corning, Tewksbury, MA) and placed at 4 × 10 per well in a total volume of 10 μL. 3 Cells were incubated with the test compound in the dark at room temperature for 1 hour to measure cAMP accumulation. The product is measured using a Cisbio HiRange cAMP assay kit (Bedford, MA) according to the manufacturer's protocol. Anti-cAMP antibody and d2-cAMP tracer reagent diluted in lysis / detection buffer are incubated in the dark for 1 hour, and the results are measured using an Envision plate reader (Perkin Elmer, Waltham, MA). Data are normalized using 1 nM GLP-1 as 100% activity and DMSO alone as 0% activity.

[0434] [Table 9] JPEG2026009897000029.jpg237101JPEG2026009897000030.jpg236101JPEG2026009897000031.jpg96111 [Table 10] JPEG2026009897000033.jpg184126

[0435] Example 6. 125 Evaluation of binding activity to human GIPR using [I]-GIP (1) Construction of an expression plasmid for the human GIPR gene The human GIPR gene, which has the same sequence as Genebank accession number U39231, is cloned into the pcDNA3.3 vector to prepare hGIPR / pcDNA3.3.

[0436] Example 7 - Preparation of human GIPR virus-like particles (VLPs) using Expi293F cells The day before transfection, 1.8 x 10 6 850 mL of Expi293F cells at a concentration of 100 cells / mL in a 3-L flask (Corning Incorporated) The cells were seeded onto 50 mL of opti-MEM and cultured at 37°C, 8% CO2, and 85 RPM for 24 hours. Transfection was performed using the Expi293 Expression System Kit (Thermo Fisher Scientific). Specifically, 0.67 mg of pcDNA3.3 / hGIPR and 0.33 mg of pcDNA3.3 / GAG plasmids for VLP preparation were added to 50 mL of opti-MEM (Thermo Fisher Scientific) to prepare a DNA mixture. Next, 2.7 mL of Expifectamine was added to 50 mL of opti-MEM and allowed to stand for 5 minutes. The DNA mixture was then mixed into the mixture, allowed to stand for 20 minutes, and then added to the medium. Twenty hours after transfection, 5 mL of Enhancer 1 and 50 mL of Enhancer 2 were added. Ninety-six hours after transfection, the medium was centrifuged at 850 × g for 15 minutes to obtain the supernatant. The resulting supernatant was ultracentrifuged at 54,000 × g for 1 hour to obtain the GIPR-VLP fraction. The precipitate was washed once with PBS and then suspended in a small amount of PBS to obtain GIPR-VLPs. The resulting GIPR-VLPs were stored at -80 °C until use. Protein quantification was performed using GelCode Blue Safe Protein Stain (Thermo Fisher Scientific) with BSA as the standard.

[0437] Example 8 - Determination of binding activity of test compounds to human GIPR. For the measurement of binding activity to GIPR, a final concentration of 100 pM [ 125 [I] GIP (PerkinElmer, Inc.) and the test compound at the indicated concentration were mixed with GIPR-VLP in assay buffer (50 mM HEPES (pH 7.4, WAKO 342-01375), 5 mM EGTA (WAKO 346-01312), 5 mM MgCl2 (WAKO 136-03995), 0.1% BSA (Merckillipore 81-066-04), and 0.005% Tween 20 (BioRad 170-6531)) and incubated at room temperature for 2 hours. 125[I] GIP-bound VLPs are captured onto a GF / C glass fiber filter 96-well plate (PerkinElmer 6005274) using a cell harvester and washed with assay buffer. The GF / C glass fiber filter 96-well plate with captured VLPs is dried overnight at 42°C. MicroScint-O (PerkinElmer 6013611) is then added to the GF / C glass fiber filter 96-well plate sealed using a back seal, and the plate is sealed using a top seal. The radioactivity of each well is finally measured using a Topcount (PerkinElmer), and the binding activity of the test compound to GIPR is determined as [I] in the presence of GIP at a final concentration of 1 μM. 125 I] GIP binding activity is 100% and the [ 125 I]GIP binding activity is calculated as 0%.

[0438] Example 9 - Evaluation of peptide agonist activity for human GIPR and human GLP1R by measuring intracellular cAMP accumulation GIPR assay HEK-293T cells overexpressing full-length human GIPR with an N-terminal FLAG tag and a sequence identical to GenBank accession number NM_000164 are purchased from Multispan, Inc. (Hayward, CA). Cells are cultured in DMEM containing 10% fetal bovine serum and 1 μg / mL puromycin according to the manufacturer's protocol and stored in frozen aliquots for use as assay-ready cells. On the day of the assay, cells are removed from frozen storage, washed twice with 1x Krebs-Ringer buffer (Zenbio, Research Triangle Park, NC), and cultured at 4 x 10 in 1x Krebs-Ringer buffer. 5 Resuspend to a concentration of 3 x 10 cells / mL. -10 ~5.08×10 -1550 nL of test compound in 100% DMSO spanning a final concentration range of 10 M was acoustically dispensed in small volumes into a white 384-well polypropylene plate (Corning, Tewksbury, MA) and placed at 4 × 10 per well in a total volume of 10 μL. 3 Add cells Cells are incubated with test compounds in the dark for 1 hour at room temperature, and cAMP accumulation is measured using a Cisbio HiRange cAMP Assay Kit (Bedford, MA) according to the manufacturer's protocol. Anti-cAMP antibody and d2-cAMP tracer reagent diluted in lysis / detection buffer are incubated in the dark for 1 hour, and results are measured using an Envision plate reader (Perkin Elmer, Waltham, MA). Data are normalized using 1 nM GIP as 100% activity and DMSO alone as 0% activity.

[0439] Example 10 In vivo effects of GIP receptor agonist peptides on emesis in a morphine-induced emesis model in live male ferrets Effect of subcutaneously administered GIP receptor agonist peptides in a morphine-induced acute emesis model. To evaluate the antiemetic effect, GIP receptor agonist peptides other than native human GIP were subcutaneously administered to male ferrets 30 minutes before morphine administration. The GIP receptor agonist peptide compounds of the present disclosure were administered at a dose of 30 nmol / kg, completely attenuating morphine (0.6 mg / kg, sc)-induced emesis in ferrets. The ferrets' condition was monitored for up to 60 minutes after morphine administration, and the frequency and time of abdominal contractions, vomiting, tongue licking, and restlessness were recorded.

[0440] Effect of subcutaneously administered selective GIP agonist peptides on morphine-induced acute emesis model Test solutions were prepared by dissolving 30 nmol / kg of GIP receptor agonist peptide in vehicle (0.09 w / v% Tween 80 / 10% DMSO / saline). Ferrets (four animals per group) were subcutaneously administered 0.5 mg / kg of the test solution or vehicle. 0.6 mg / kg of morphine was administered subcutaneously every four hours after administration. The ferrets were monitored for up to 60 minutes after morphine administration, recording the number of animals that did not vomit, the number of emetic episodes, the latency period (in minutes) for observing an emetic episode, and the duration of vomiting, if any.

[0441] Formulation Example 1 (1)Compound 10 10.0mg (2) Lactose 70.0 mg (3) Cornstarch 50.0mg (4) Soluble starch 7.0mg (5) Magnesium stearate 3.0 mg

[0442] Compound 10 (10.0 mg) and magnesium stearate (3.0 mg) are granulated with a soluble starch aqueous solution (0.07 mL) (7.0 mg as soluble starch), dried, and mixed with lactose (70.0 mg) and corn starch (50.0 mg). The mixture is compressed to obtain tablets.

[0443] Formulation Example 2 (1) Compound 5 5.0mg (2) Sodium chloride 20.0 mg (3) Distilled water up to a total volume of 2 mL

[0444] Compound 5 (5.0 mg) and sodium chloride (20.0 mg) are dissolved in distilled water, and water is added to make the total volume 2.0 ml. The solution is filtered and aseptically filled into 2 ml ampoules. The ampoules are sterilized and tightly sealed to form a solution for injection. [Industrial Applicability]

[0445] The GIP receptor agonist peptides of the present disclosure have excellent GIP receptor selective agonist activity and are useful as drugs for the prevention or treatment of emesis and conditions caused in association with GIP receptor activity, such as diseases associated with emesis and vomiting and nausea, etc. In one embodiment, the selective GIP receptor agonist peptides are useful as drugs or pharmaceuticals, or for use in the prevention or treatment of emesis and conditions caused in association with GIP receptor activity, such as cyclic vomiting, and nausea and / or vomiting associated with the administration of chemotherapeutic agents or anticancer agents as described herein.

[0446] All publications, patents, and patent applications cited herein are hereby incorporated by reference in their entirety.

[0447] Sequence Listing Free Text SEQ ID NO: 1: Native human GIP (1-42 peptide) SEQ ID NO: 2: Native human GIP (1-153, signal peptide: 1-21, propeptide: 22-50, peptide: 52-93, propeptide: 95-153) SEQ ID NO: 3: mRNA sequence of native human GIP of SEQ ID NO: 2. SEQ ID NOs: 4-11: Reference GIP receptor agonist peptides (Formulas I-VIII) SEQ ID NOs: 12 to 281 Synthetic peptides (Formulas (I) to (VIII)) Other embodiments

[0448] While the present invention has been described in conjunction with its detailed description, it should be understood that the foregoing description is intended to illustrate, but not to limit, the scope of the invention as defined by the appended claims. Other aspects, advantages, and modifications are within the scope of the claims.

Claims

1. Formula (I): P １ -A1-A2-A3-A4-A5-A6-A7-A8-A9-A10-A11-A12-A13-A14-A15-A16-A17-A18-A19-A20-A21-A2 2-A23-A24-A25-A26-A27-A28-A29-A30-A31-A32-A33-A34-A35-A36-A37-A38-A39-A40-A41-P ２ (SEQ ID NO: 4), or a salt thereof, During the ceremony, P １ teeth, -R Ａ１ 、 -CO-R Ａ１ 、 -CO-OR Ａ１ 、 - CO - COLOR Ａ１ 、 -SO-R Ａ１ 、 -SO ２ -R Ａ１ 、 -SO ２ -OR Ａ１ 、 -CO-NR Ａ２ R Ａ３ 、 -SO ２ -NR Ａ２ R Ａ３ 、 -C(=NR) Ａ１ )-NR Ａ２ R Ａ３ or represents a group of the formula Does not exist, R Ａ１ , R Ａ２ , and R Ａ３ each independently represents a hydrogen atom, an optionally substituted hydrocarbon group, or an optionally substituted heterocyclic group; P ２ is -NH ２ or represents —OH, A1 represents Tyr, 3,5-Dix Tyr, D-Tyr, 3,5 di-Br-Tyr, Phe, alpha methyl-Phe, mono-halo-Phe, bis-halo-Phe, -Tyr, -D-Phe, -D-Tyr, des-amino-Phe, or des-amino-Tyr; A2 represents Aib, Ala, Gly, Sar, Abu, or D-Ala; A3 represents Glu or Pro; A4 represents Gly or Ser; A5 represents Thr, D-Iva, Glu, Iva, or Ser; A6 represents Ala, Aib, alpha-methyl-Phe, A6C, Glu, Iva, Arg, Phe, or Val; A7 represents Ile, Lys, Val, Ala, AiB, α-methyl-Leu, A6C, Asp, Phe, Gly, Iva, Leu, Arg, or Ser; A8 represents Ser, Ala, AiB, Asp, Phe, Gly, Leu, or Arg; A9 represents Asp, Leu, Aib, Glu, Asn, Gln, Ser, or Phe; A10 represents Aib, α-methyl-Phe, A6C, Lys, or Tyr; A11 represents Aib Ser, Ala, Glu, Iva, A5c, A6c, or Leu; A12 represents Ile, Ala, Aib, Glu, α-methyl-Phe, Phe, Lys, Arg, Ser, Trp, A6C, Cys, or Asp; A13 represents Aib, Ala, Val, Iva, Gln, Leu, Tyr, D-Iva, α-methyl-Phe, A6C, or Glu; A14 represents Leu, Nle, Tyr, Ala, AiB, α-methyl-Leu, Lys, Leu, Ser, Met, or Me; A15 represents Ala, Aib, Leu, Asn, Asp, Glu, Lys, Ser, or Tyr; A16 represents Arg Ala, AiB, Glu, Gly, Leu, Ser, or Lys; A17 represents Aib, Ala, Lys, Asp, Arg, Gln, Glu, or Ile; A18 represents Ala, Aib, A6C, Phe, Gly, Iva, Leu, Ser, Trp, or His; A19 represents Gln, Ala, Val, AiB, Ile, Arg, or Ser; A20 represents AiB, Ala, Arg, Glu, Gly, Ser, Val, or Gln; A21 represents Asn, Asp, Glu, Leu, Ala, AiB, Lys, Gln, or Ser; A22 represents Phe, Glu, Gln, Arg, Trp, or αMePhe; A23 represents Ile, Aib, Asp, Glu, Arg, Thr, or Val; A24 represents Arg, Asn, Asp, Lys, Lys(Ac), Ala, AiB, Cys, Phe, Leu, Nle, Ser, Asp, or Gln; A25 represents Trp, Aib, α-methyl-Leu, A6C, Ile, Asn, Nle, Arg, or Val; A26 represents Aib, Iva, Ala, alpha-methyl-Leu, A6C, Ile, Asn, Nle, Arg, Val, or Leu; A27 represents Leu, Val, Ala, AiB, α-methyl-Leu, A6C, Ile, Met, Nle, Arg, Trp, or Ile; A28 represents Ala, Arg, Lys, AiB, Asp, Asn, or Lys(Ac); A29 represents Gln, Gly, Arg, Glu, Leu, or Aib; A30 represents Lys, Arg, Gly, or Glu; A31 represents Pro, Gly, Hyp, Gln, Phe, ψ, or a deletion; A32 represents Ser, Gly, Arg, Lys, ψ, or a deletion; A33 represents Ser, Gly, Pro, Lys, ψ, or a deletion; A34 represents Gly, Ser, Asn, ψ, or a deletion; A35 represents Ala, Ser, Ser, Asp, ψ, or a deletion; A36 represents Pro, Gly, Gly, Hyp, Trp, ψ, or a deletion; A37 represents Pro, Gly, Ala, Hyp, Lys, ψ, or a deletion; A38 represents Pro, Gly, Hyp, His, ψ, or a deletion; A39 represents Ser, Gly, Lys, Pro, Asn, ψ, or a deletion; A40 represents Arg, Ser, Cys, Glu, Lys, Lys-Ac, Pro, Ile, ψ, or a deletion; A41 represents Gly, Ser, Ile, Thr, ψ, or a deletion; The GIP receptor agonist peptide or a salt thereof, wherein any one or two amino acids selected from A31 to A41 optionally represent ψ, where ψ is a residue independently selected from Lys, Arg, Orn, and Cys, and the side chain of the residue is substituted, with the proviso that the GIP receptor agonist peptide is not a peptide having any one of the amino acid sequences of SEQ ID NOs: 4 to 569 disclosed in PCT / JP2018 / 013540.

2. Formula (II): P １ -T-A-2-G-G-N-T-A-6-A-7-A-8-A-9-A-10-A-11-A-12-A-13-A-14-A-15-A-16 -A17-A18-A19-A20-A21-A22-A23-A24-A25-A26-A27-A28-A29-A30-A3 1-A32-A33-A34-A35-A36-A37-A38-A39-A40-A41-P ２ 2. The GIP receptor agonist peptide according to claim 1, or a salt thereof, represented by (SEQ ID NO: 5), wherein: P １ teeth, -R Ａ１ 、 -CO-R Ａ１ 、 -CO-OR Ａ１ 、 - CO - COLOR Ａ１ 、 -SO-R Ａ１ 、 -SO ２ -R Ａ１ 、 -SO ２ -OR Ａ１ 、 -CO-NR Ａ２ R Ａ３ 、 -SO ２ -NR Ａ２ R Ａ３ ,or -C(=NR) Ａ１ )-NR Ａ２ R Ａ３ represents a group represented by the formula: R Ａ１ , R Ａ２ , and R Ａ３ each independently represents a hydrogen atom, an optionally substituted hydrocarbon group, or an optionally substituted heterocyclic group; P ２ is -NH ２ or represents —OH, A2 represents Aib or D-Ala; A6 represents Iva, Phe, or Val; A7 represents Ile, Lys, or Val, A8 represents Ser; A9 represents Asp, Leu, or Phe; A10 represents Tyr; A11 represents Aib or Ser; A12 represents Ile; A13 represents Aib, Ala, Gln, Leu, Tyr, or D-Iva; A14 represents Leu; A15 represents Asp, Glu, Lys, Ser, or Tyr; A16 represents Arg or Lys; A17 represents Aib, Gln, or Ile; A18 represents Ala or His, A19 represents Gln or Ser; A20 represents Aib, Ala, or Gln; A21 represents Asn, Asp, Glu, Leu, or Ser; A22 represents Phe or αMePhe; A23 represents Ile or Val, A24 represents Arg, Asn, Asp, Lys, or Lys(Ac); A25 represents Trp, A26 represents Aib, Iva, or Leu; A27 represents Leu; A28 represents Ala, Arg, Lys, or Lys(Ac); A29 represents Gln or Gly; A30 represents Arg or Gly; A31 represents Pro, Gly, ψ, or a deletion; A32 represents Ser, Gly, ψ, or a deletion; A33 represents Ser, Gly, ψ, or a deletion; A34 represents Gly, ψ, or a deletion; A35 represents Ala, Ser, ψ, or a deletion; A36 represents Pro, Gly, ψ, or a deletion; A37 represents Pro, Gly, ψ, or a deletion; A38 represents Pro, Gly, ψ, or a deletion; A39 represents Ser, Gly, ψ, or a deletion; A40 represents Arg, Ser, ψ, or a deletion; A41 represents Gly, ψ, or a deletion; The GIP receptor agonist peptide or a salt thereof, wherein any one or two amino acids selected from A31 to A41 optionally represent ψ, where ψ is a residue independently selected from Lys, Arg, Orn, and Cys, and the side chain of the residue is substituted, with the proviso that the GIP receptor agonist peptide is not a peptide having any one of the amino acid sequences of SEQ ID NOs: 4 to 569 disclosed in PCT / JP2018 / 013540.

3. Formula (III): P １ -Tyr-A2-Glu-Gly-Thr-A6-A7-A8-A9-A10-A11-A12-A13-A14-A15-A16-A17-A18-A19-A20-A21- A22-A23-A24-A25-A26-A27-A28-A29-A30-A31-A32-A33-A34-A35-A36-A37-A38-A39-A40-A41-P ２ 2. The GIP receptor agonist peptide according to claim 1, represented by (SEQ ID NO: 6), or a salt thereof, wherein: P １ teeth, -R Ａ１ 、 -CO-R Ａ１ 、 -CO-OR Ａ１ 、 - CO - COLOR Ａ１ 、 -SO-R Ａ１ 、 -SO ２ -R Ａ１ 、 -SO ２ -OR Ａ１ 、 -CO-NR Ａ２ R Ａ３ 、 -SO ２ -NR Ａ２ R Ａ３ ,or -C(=NR) Ａ１ )-NR Ａ２ R Ａ３ represents a group represented by the formula: R Ａ１ , R Ａ２ , and R Ａ３ each independently represents a hydrogen atom, an optionally substituted hydrocarbon group, or an optionally substituted heterocyclic group; P ２ is -NH ２ or represents —OH, A2 represents Aib or D-Ala; A6 represents Iva, Phe, or Val; A7 represents Ile, Lys, or Val, A8 represents Ser; A9 represents Asp, Leu, or Phe; A10 represents Tyr; A11 represents Aib or Ser; A12 represents Ile; A13 represents Aib, Ala, Gln, Leu, Tyr, or D-Iva; A14 represents Leu; A15 represents Asp, Glu, Lys, Ser, or Tyr; A16 represents Arg or Lys; A17 represents Aib, Gln, or Ile; A18 represents Ala or His, A19 represents Gln or Ser; A20 represents Aib, Ala, or Gln; A21 represents Asn, Asp, Glu, Leu, or Ser; A22 represents Phe or αMePhe; A23 represents Ile or Val, A24 represents Arg, Asn, Asp, Lys, or Lys(Ac); A25 represents Trp, A26 represents Aib, Iva, or Leu; A27 represents Leu; A28 represents Ala, Arg, Lys, or Lys(Ac); A29 represents Gln or Gly; A30 represents Arg or Gly; A31 represents Pro, Gly, ψ, or a deletion; A32 represents Ser, Gly, ψ, or a deletion; A33 represents Ser, Gly, ψ, or a deletion; A34 represents Gly, ψ, or a deletion; A35 represents Ala, Ser, ψ, or a deletion; A36 represents Pro, Gly, ψ, or a deletion; A37 represents Pro, Gly, ψ, or a deletion; A38 represents Pro, Gly, ψ, or a deletion; A39 represents Ser, Gly, ψ, or a deletion; A40 represents Arg, Ser, ψ, or a deletion; A41 represents Gly, ψ, or a deletion; The GIP receptor agonist peptide or a salt thereof, wherein any one or two amino acids selected from A31 to A41 optionally represent ψ, where ψ is a residue independently selected from Lys, Arg, Orn, and Cys, and the side chain of the residue is substituted, with the proviso that the GIP receptor agonist peptide is not a peptide having any one of the amino acid sequences of SEQ ID NOs: 4 to 569 disclosed in PCT / JP2018 / 013540.

4. Formula (IV): P １ -A1-A2-Glu-Gly-Thr-A6-A7-A8-A9-A10-A11-A12-A13-A14-A15-A16-A17-A18-A19-A20-A21-A 22-A23-A24-A25-A26-A27-A28-A29-A30-A31-A32-A33-A34-A35-A36-A37-A38-A39-A40-A41-P ２ 2. The GIP receptor agonist peptide according to claim 1, represented by (SEQ ID NO: 7), or a salt thereof, wherein: P １ teeth, -R Ａ１ 、 -CO-R Ａ１ 、 -CO-OR Ａ１ 、 - CO - COLOR Ａ１ 、 -SO-R Ａ１ 、 -SO ２ -R Ａ１ 、 -SO ２ -OR Ａ１ 、 -CO-NR Ａ２ R Ａ３ 、 -SO ２ -NR Ａ２ R Ａ３ ,or -C(=NR) Ａ１ )-NR Ａ２ R Ａ３ represents a group represented by the formula: R Ａ１ , R Ａ２ , and R Ａ３ each independently represents a hydrogen atom, an optionally substituted hydrocarbon group, or an optionally substituted heterocyclic group; P ２ is -NH ２ or represents —OH, A1 represents Tyr; A2 represents Aib or D-Ala; A6 represents Iva, Phe, or Val; A7 represents Ile, Lys, or Val, A8 represents Ser; A9 represents Asp, Leu, or Phe; A10 represents Tyr; A11 represents Aib or Ser; A12 represents Ile; A13 represents Aib, Ala, Gln, Leu, Tyr, or D-Iva; A14 represents Leu; A15 represents Asp, Glu, Lys, Ser, or Tyr; A16 represents Arg or Lys; A17 represents Aib, Gln, or Ile; A18 represents Ala or His, A19 represents Gln or Ser; A20 represents Aib, Ala, or Gln; A21 represents Asn, Asp, Glu, Leu, or Ser; A22 represents Phe or αMePhe; A23 represents Ile or Val, A24 represents Arg, Asn, Asp, Lys, or Lys(Ac); A25 represents Trp, A26 represents Aib, Iva, or Leu; A27 represents Leu; A28 represents Ala, Arg, Lys, or Lys(Ac); A29 represents Gln or Gly; A30 represents Arg; A31 represents Pro, Gly, ψ, or a deletion; A32 represents Ser, Gly, ψ, or a deletion; A33 represents Ser, Gly, ψ, or a deletion; A34 represents Gly, ψ, or a deletion; A35 represents Ala, Ser, ψ, or a deletion; A36 represents Pro, Gly, ψ, or a deletion; A37 represents Pro, Gly, ψ, or a deletion; A38 represents Pro, Gly, ψ, or a deletion; A39 represents Ser, Gly, ψ, or a deletion; A40 represents Arg, Ser, ψ, or a deletion; A41 represents Gly, ψ, or a deletion; The GIP receptor agonist peptide or a salt thereof, wherein any one or two amino acids selected from A31 to A41 optionally represent ψ, where ψ is a residue independently selected from Lys, Arg, Orn, and Cys, and the side chain of the residue is substituted, with the proviso that the GIP receptor agonist peptide is not a peptide having any one of the amino acid sequences of SEQ ID NOs: 4 to 569 disclosed in PCT / JP2018 / 013540.

5. A1-A2-Glu-Gly-Thr-A6-A7-A8-A9-A10-A11-A12-A13-A14-A15-A16-A17-A18-A19-A20-A21-A22-A23-A24-A25 in formula (I) -A26-A27-A28-A29 is Tyr-Aib-Glu-Gly-Thr-Phe-Ile-Ser-Asp-Tyr-Ser-Ile-Ala-Leu-Asp-Arg-Aib-His-Gln-Aib-As 2. The GIP receptor agonist peptide according to claim 1, or a salt thereof, represented by formula (V), which is n-Phe-Val-Asn-Trp-Iva-Leu-Ala-Gln (SEQ ID NO: 8), provided that the GIP receptor agonist peptide or a salt thereof is not a peptide having any one of the amino acid sequences of SEQ ID NOs: 4 to 569 disclosed in PCT / JP2018 / 013540.

6. Formula (VI): P １ -Tyr-Aib-Glu-Gly-Thr-Phe-Ile-Ser-Asp-Tyr-Ser-Ile-Ala-Leu-Asp-Arg-Aib-His-Gln-Aib-As n-Phe-Val-Asn-Trp-Iva-Leu-Ala-Gln-A30-A31-A32-A33-A34-A35-A36-A37-A38-A39-A40-A41-P ２ 2. The GIP receptor agonist peptide according to claim 1, or a salt thereof, represented by (SEQ ID NO: 9): During the ceremony, P １ teeth, -R Ａ１ 、 -CO-R Ａ１ 、 -CO-OR Ａ１ 、 - CO - COLOR Ａ１ 、 -SO-R Ａ１ 、 -SO ２ -R Ａ１ 、 -SO ２ -OR Ａ１ 、 -CO-NR Ａ２ R Ａ３ 、 -SO ２ -NR Ａ２ R Ａ３ ,or -C(=NR) Ａ１ )-NR Ａ２ R Ａ３ represents a group represented by the formula: R Ａ１ , R Ａ２ , and R Ａ３ each independently represents a hydrogen atom, an optionally substituted hydrocarbon group, or an optionally substituted heterocyclic group; P ２ is -NH ２ or represents —OH, A30 represents Arg; A31 represents Pro, Gly, or Lys(R); A32 represents Ser, Gly, or Lys(R); A33 represents Ser, Gly, or Lys(R); A34 represents Gly or Lys(R); A35 represents Ala, Ser, or Lys(R); A36 represents Pro, Gly, or Lys(R); A37 represents Pro, Gly, Lys(R), or a deletion; A38 represents Pro, Gly, Lys(R), or a deletion; A39 represents Ser, Gly, Lys(R), or a deletion; A40 represents Arg, Ser, Lys(R), or a deletion; A41 represents Gly, Lys(R), or a deletion; The GIP receptor agonist peptide or a salt thereof, wherein any one or two amino acids selected from A31 to A41 optionally represent Lys(R), where (R) represents a substituent, and the GIP receptor agonist peptide is not a peptide having an amino acid sequence of any one of SEQ ID NOs: 4 to 569 disclosed in PCT / JP2018 / 013540.

7. Formula (VII): P １ -Tyr-Aib-Glu-Gly-Thr-Phe-Ile-Ser-Asp-T yr-Ser-Ile-Ala-Leu-Asp-Arg-Aib-His-Gln-Aib-Asn-Phe-Val-Asn-T rp-Iva-Leu-Ala-Gln-A30-A31-A32-A33-A34-A35-A36-A37-A38-A39-P ２ 2. The GIP receptor agonist peptide according to claim 1, represented by (SEQ ID NO: 10), or a salt thereof, wherein: P １ teeth, -R Ａ１ 、 -CO-R Ａ１ 、 -CO-OR Ａ１ 、 - CO - COLOR Ａ１ 、 -SO-R Ａ１ 、 -SO ２ -R Ａ１ 、 -SO ２ -OR Ａ１ 、 -CO-NR Ａ２ R Ａ３ 、 -SO ２ -NR Ａ２ R Ａ３ ,or -C(=NR) Ａ１ )-NR Ａ２ R Ａ３ represents a group represented by the formula: R Ａ１ , R Ａ２ , and R Ａ３ each independently represents a hydrogen atom, an optionally substituted hydrocarbon group, or an optionally substituted heterocyclic group; P ２ is -NH ２ or represents —OH, A30 represents Arg; A31 represents Pro, Gly, or Lys(R); A32 represents Ser, Gly, or Lys(R); A33 represents Ser, Gly, or Lys(R); A34 represents Gly or Lys(R); A35 represents Ala, Ser, or Lys(R); A36 represents Pro, Gly, or Lys(R); A37 represents Pro, Gly, or Lys(R); A38 represents Pro, Gly, Lys(R); A39 represents Ser, Gly, or Lys(R); wherein any one or two amino acids selected from A31 to A39 optionally represent Lys(R), and (R) represents a substituent or a salt thereof.

8. Formula (VIII): P １ -Tyr-Aib-Glu-Gly-Thr-Phe-Ile-Ser-Asp-Tyr-Ser-Ile-Ala-Leu-Asp-Arg-Aib-His-Gln-Aib- Asn-Phe-Val-Asn-Trp-Iva-Leu-Ala-Gln-A30-A31-A32-A33-A34-A35-A36-A37-A38-A39-A40-P ２ 2. The GIP receptor agonist peptide according to claim 1, represented by (SEQ ID NO: 11), or a salt thereof, wherein: P １ teeth, -R Ａ１ 、 -CO-R Ａ１ 、 -CO-OR Ａ１ 、 - CO - COLOR Ａ１ 、 -SO-R Ａ１ 、 -SO ２ -R Ａ１ 、 -SO ２ -OR Ａ１ 、 -CO-NR Ａ２ R Ａ３ 、 -SO ２ -NR Ａ２ R Ａ３ ,or -C(=NR) Ａ１ )-NR Ａ２ R Ａ３ represents a group represented by the formula: R Ａ１ , R Ａ２ , and R Ａ３ each independently represents a hydrogen atom, an optionally substituted hydrocarbon group, or an optionally substituted heterocyclic group; P ２ is -NH ２ or represents —OH, A30 represents Arg; A31 represents Pro, Gly, or Lys(R); A32 represents Ser, Gly, or Lys(R); A33 represents Ser, Gly, or Lys(R); A34 represents Gly or Lys(R); A35 represents Ala, Ser, or Lys(R); A36 represents Pro or Lys(R); A37 represents Pro or Lys(R); A38 represents Pro or Lys(R); A39 represents Ser or Lys(R); A40 represents Arg or Ser; wherein any one or two amino acids selected from A31 to A39 optionally represent Lys(R), and (R) represents a substituent or a salt thereof.

9. 9. The GIP receptor agonist peptide of claim 1, wherein ψ is a residue independently selected from Lys, Arg, Orn, and Cys, and the side chain of said residue is substituted with X-L-; or (R) is represented by X-L-, wherein L represents a bond or a divalent substituent, and X represents an optionally substituted hydrocarbon group or a salt thereof.

10. 9. The GIP receptor agonist peptide of claim 1, wherein ψ is a Lys residue having a side chain substituted with XL-.

11. L is (PEG3)2, Abu-, (Gly) （２－８） -, gGlu （１－３） - or a combination thereof.

12. 11. The GIP receptor agonist peptide of claim 9, wherein L represents (PEG3)2-gGlu-.

13. 12. The GIP receptor agonist peptide of claim 11, wherein L represents Abu-gGlu-.

14. L is (Gly) ５ -gGlu- or (Gly) ６ 12. The GIP receptor agonist peptide of claim 11, which represents -gGlu-.

15. 10. The GIP receptor agonist peptide of claim 9, wherein L represents GGGGG-.

16. 10. The GIP receptor agonist peptide of claim 9, wherein L represents (PEG3)2-.

17. L is (PEG3)2-(Gly) ５－６ The GIP receptor agonist peptide of claim 9, wherein

18. L represents a bond or a divalent substituent, X represents an optionally substituted hydrocarbon group or 18. The GIP receptor agonist peptide of any one of claims 9 to 17, which is a salt.

19. 19. The GIP receptor agonist peptide of claim 18, wherein the divalent substituent 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 a combination thereof.

20. X is C ６ ~C ２０ Monoacid, C ６ ~C ２０ 20. The GIP receptor agonist peptide of any one of claims 9 to 19, which is a diacid or acetyl group.

21. 21. The GIP receptor agonist peptide of claim 20, wherein X is (Trda: C13 diacid), (Teda: C14 diacid), (Peda: C15 diacid), (Heda: C16 diacid), (Hepda: C17 diacid), (Oda: C18 diacid), or (Eda: C20 diacid) (Ida: C___ diacid).

22. ψ or (R) is -(g-Glu) ２ -Oda, -(g-Glu) ２ -Eda, -(g-Glu) ２ -Heda, -(PEG3)2-gGlu-Eda, -(PEG3)2-gGlu-Heda, -(PEG3)2-gGlu-Oda, -(PEG3)2-gGlu- Ida, -(PEG3)-gGlu-Eda, -(PEG3)-gGlu-Heda, -(PEG3)-gGlu-Oda, -Abu-gGlu-Oda, -(Gly) ５ -gGlu-Eda, -(Gly) ５ -gGlu-Heda, -(Gly) ５ -gGlu-Oda, -(Gly) ５ -Heda, -(Gly) ５ -Oda, -(Gly) ５ 22. The GIP receptor agonist peptide of any one of claims 9 to 21, which represents -Eda, -(PEG3)2-Heda, -(PEG3)2-Eda, -(PEG3)2-Oda, or a combination thereof.

23. The GIP receptor agonist peptides may be more than 10, or more than 100, or more than 1,000, or more than 100,000. ５０ / GIPR EC ５０ 23. The GIP receptor agonist peptide of any one of claims 1 to 22, having a selectivity ratio expressed as a ratio of 1 / (GIP receptor agonist activity) / (GIP receptor agonist activity).

24. The GIP receptor agonist peptide according to any one of claims 1 to 23, wherein the GIP receptor agonist peptide, or a medicament comprising the GIP receptor agonist peptide, or a pharmaceutical composition comprising the GIP receptor agonist peptide, is administered to treat emesis as a monotherapy.

25. A pharmaceutical comprising the GIP receptor agonist peptide or a salt thereof according to any one of claims 1 to 23.

26. 26. The pharmaceutical of claim 25, which is an activator of the GIP receptor.

27. 27. The pharmaceutical of claim 26, which is an anti-vomiting or nausea agent.

28. Use of the GIP receptor agonist peptide or a salt thereof according to any one of claims 1 to 23 for the manufacture of an antiemetic or antinausea agent.

29. 24. The peptide or salt thereof according to any one of claims 1 to 23 for use in suppressing vomiting or nausea.

30. A method for preventing or treating emesis in a subject, the method comprising administering to the subject an effective amount of the peptide or salt thereof according to any one of claims 1 to 23.

31. 31. The method of claim 30, wherein the emesis is nausea and / or vomiting.

32. The medicament according to claim 25, the use according to claim 28, the peptide according to claim 29, or the method according to claim 30, wherein the emesis, vomiting, or nausea is caused by one or more conditions or causes selected from the following (1) to (10): (1) Diseases accompanied by vomiting or nausea, such as gastroparesis, gastrointestinal hypomotility, peritonitis, abdominal tumors, 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 lesions, metabolic disorders, infectious gastritis, postoperative diseases, myocardial infarction, migraine, intracranial hypertension, and intracranial hypotension (e.g., altitude sickness), (2)(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), metabolic inhibitors (e.g., cytarabine, methotrexate, 5-fluorouracil, enocitabine, and clofarabine). (ii) other chemotherapeutic agents such as vinca alkaloids (e.g., etoposide, vinblastine, and vincristine), cisplatin, procarbazine, hydroxyurea, azacitidine, irinotecan, interferon alpha, interleukin-2, oxaliplatin, carboplatin, nedaplatin, and miriplatin; (ii) opioid analgesics (e.g., morphine); (iii) dopamine receptor D1D2 agonists (e.g., apomorphine); (iv) vomiting and / or nausea induced by chemotherapeutic agents such as cannabis and cannabinoid products (including cannabis hypersensitivity syndrome); (3) Vomiting or nausea caused by radiation damage or radiation therapy to the chest, abdomen, etc. used to treat cancer; (4) Vomiting or nausea caused by a toxic substance or toxin; (5) Vomiting and nausea caused by pregnancy, including hyperemesis gravidarum; (6) Vomiting and nausea caused by vestibular disorders such as motion sickness and dizziness, (7) opioid withdrawal, (8) Pregnancy, including hyperemesis gravidarum; (9) vestibular disorders such as motion sickness or dizziness, or (10) Physical injury causing localized, generalized, acute or chronic pain.

33. 31. The method of claim 30, wherein the emesis is a result of cyclic vomiting syndrome or chemotherapy.

34. 31. The method of claim 30, wherein the subject is a non-type 2 diabetic subject.

35. 31. The method of claim 30, wherein the vomiting is delayed or anticipatory vomiting.

36. 36. The method of any one of claims 30 to 35, wherein the method treats vomiting in the subject without inducing anxiety or sedation in the subject.

37. Induces suppression of glucagon secretion when plasma glucose levels exceed fasting levels 37. The method of any one of claims 30 to 36, wherein vomiting is treated in the subject without administering an anticoagulant.

38. 37. The method of any one of claims 30 to 36, wherein emesis is treated in the subject without substantially activating the GLP-1 receptor.

39. 39. The method of any one of claims 30 to 38, wherein emesis is treated in the subject without the concomitant, subsequent, or prior administration of a GLP-1 receptor agonist.

40. 40. The method of any one of claims 30 to 39, wherein emesis is treated in a subject who is not taking a medication for controlling a metabolic syndrome disorder.

41. 40. The method of any one of claims 30 to 39, wherein emesis is treated in a subject taking a medication for controlling a metabolic syndrome disorder.

42. 42. The method of claim 41, wherein the metabolic syndrome disorder is type 2 diabetes or obesity.

43. 43. The method of any one of claims 30 to 42, wherein the vomiting is caused by cyclic vomiting or chemotherapy-associated nausea or vomiting, or the vomiting causes cyclic vomiting or chemotherapy-associated nausea or vomiting.

44. The chemotherapy or chemotherapeutic agent is (i) an alkylating agent (e.g., cyclophosphamide, carmustine, lomustine, chlorambucil, streptozocin, dacarbazine, ifosfamide, temozolomide, busulfan, bendamustine, and melphalan), a cytotoxic antibiotic (e.g., dactinomycin, doxorubicin, mitomycin-C, bleomycin, epirubicin, actinomycin D, amrubicin, idarubicin, daunorubicin, and pirarubicin), an anti-metabolic agent (e.g., cytarabine, methotrexate, 5-fluorouracil, enocitabine, and and clofarabine), vinca alkaloids (e.g., etoposide, vinblastine, and vincristine), cisplatin, procarbazine, hydroxyurea, azacitidine, irinotecan, interferon alpha, interleukin-2, oxaliplatin, carboplatin, nedaplatin, and miriplatin; (ii) other chemotherapeutic agents such as opioid analgesics (e.g., morphine); (iii) dopamine receptor D1D2 agonists (e.g., apomorphine); (iv) cannabis and cannabinoid products (including cannabis hypersensitivity syndrome).

45. The method of any one of claims 30 to 44, wherein the subject has type 2 diabetes.

46. 46. ​​The method of any one of claims 30 to 45, wherein the GIP receptor agonist peptide or medicament is administered subcutaneously, intravenously, intramuscularly, intraperitoneally, orally, or by inhalation.

47. 47. The method of any one of claims 30-46, wherein the effective amount of the GIP receptor agonist peptide administered to the subject is about 0.01-0.5 mg / kg / day, 0.1-5 mg / kg / day, 5-10 mg / kg / day, 10-20 mg / kg / day, 20-50 mg / kg / day, 10-100 mg / kg / day, 10-120 mg / kg / day, 50-100 mg / kg / day, 100-200 mg / kg / day, 200-300 mg / kg / day, 300-400 mg / kg / day, 400-500 mg / kg / day, 500-600 mg / kg / day, 600-700 mg / kg / day, 700-800 mg / kg / day, 800-900 mg / kg / day, or 900-1000 mg / kg / day.

48. The method of any one of claims 30 to 47, wherein the subject is a human.

49. 49. The method of any one of claims 30 to 48, wherein the GIP receptor agonist peptide or medicament is administered to the subject before, during or after the elephant develops a pathological condition.

50. 50. The method of any one of claims 30 to 49, wherein the GIP receptor agonist peptide or medicament is administered to the subject 1 to 3 times daily or 1 to 7 times weekly.

51. 51. The method of any one of claims 30 to 50, wherein the GIP receptor agonist peptide or medicament is administered to the subject for 1 to 5 days, 1 to 5 weeks, 1 to 5 months, or 1 to 5 years.

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