Medication regime

Abstract

The present invention relates to dosing regimes of compounds having agonist activity at the GLP-1 (glucagon-like peptide 1) and GLP-2 (glucagon-like peptide 2) receptors for use in the treatment of obesity and related conditions.

Description

[Technical Field]

[0001] The present invention relates to a therapeutic method using acylated compounds having dual agonist activity at GLP-1 (glucagon-like peptide 1) and GLP-2 (glucagon-like peptide 2) receptors. More specifically, the present invention relates to a drug regimen of dual GLP-1 / GLP-2 agonist peptides for weight regulation and prevention or treatment of obesity and related conditions. [Background technology]

[0002] Obesity is currently a significant public health problem across much of the developed world and is associated with the development of several serious conditions, including cardiovascular disease, type 2 diabetes, sleep apnea, and certain cancers. The standard treatment for obesity is lifestyle intervention, including reduced energy intake and increased exercise. However, while such interventions can achieve temporary success, it is often difficult for patients to maintain such lifestyle changes over the long term so that the achieved weight loss is sustainable.

[0003] GLP-1 is released from the intestines in response to food intake and therefore acts as a satiety signal, leading to reduced food intake (Madsbad, S., 2014, Diabetes Obes Metab, 16: 9-21). Evidence exists suggesting that the effects of GLP-1 may be impaired in obese subjects, suggesting that GLP-1 agonists may have potential in the treatment of obesity. However, a significant drawback of GLP-1 therapy is that a considerable proportion of patients taking known GLP-1 agonists suffer from nausea and vomiting as side effects (Filippatos et al, 2014 / 15, Rev Diabet Stud., 11(3): 202-230). These side effects generally require gradually increasing the dose of GLP-1 agonists from a low starting dose to minimize such side effects. In fact, recent clinical trial data for the GLP-1 agonist semaglutide show that nausea and vomiting were commonly observed in patients, even when the drug was initially administered at low doses (Wilding et al, 2021, N Engl J Med; 384:989-1002). These side effects are undesirable because they tend to reduce patient compliance with treatment.

[0004] Therefore, there is a continued need for therapeutic agents with GLP-1 agonist activity that are effective in treating obesity and related conditions, while not causing the expected side effects of nausea and vomiting during administration.

[0005] WO2018 / 104561 discloses a peptide with dual GLP-1 and GLP-2 agonist activity and proposes its medical use. However, it does not disclose a specific drug regime for the treatment of obesity and related conditions.

[0006] Surprisingly, it was found that administration of a specific peptide having dual GLP-1 and GLP-2 agonist activity at a particular dosage resulted in decreased appetite in patients without causing the expected side effects of nausea and vomiting. As described herein, the appetite-suppressing effect of dual GLP-1 and GLP-2 agonists can occur before (i.e., at lower doses) nausea and vomiting. This is advantageous compared to known GLP-1 agonist treatments, where gastrointestinal adverse events (nausea and vomiting) occur before (i.e., at lower doses) decreased satiety. This suggests that dual GLP-1 and GLP-2 agonists may have a better safety profile with respect to gastrointestinal adverse events in indications where appetite suppression is desired. Therefore, the dosage regime of the present invention represents a significant advance over known GLP-1 agonist treatments for obesity. [Prior art documents] [Patent Documents]

[0007] [Patent Document 1] WO2018 / 104561 [Non-patent literature]

[0008] [Non-Patent Document 1] Madsbad, S., 2014, Diabetes Obes Metab, 16: 9-21 [Non-Patent Document 2] Filippatos et al, 2014 / 15, Rev Diabet Stud., 11(3): 202-230 [Non-Patent Document 3] Wilding et al, 2021, N Engl J Med; 384:989-1002 [Overview of the project] [Problems that the invention aims to solve]

[0009] In general, the present invention relates to compounds having agonist activity at GLP-1 (glucagon-like peptide 1) and GLP-2 (glucagon-like peptide 2) receptors, as evaluated, for example in an in vitro efficacy assay, for use in methods of reducing or inhibiting weight gain, reducing food intake, reducing appetite, promoting weight loss, or treating obesity, morbid obesity, obesity-related gallbladder disease, or obesity-induced sleep apnea. Such compounds are referred to herein as "GLP-1 / GLP-2 dual agonists" or simply "dual agonists." Accordingly, the compounds according to the present invention have activity at both GLP-1 (7-36) and GLP-2 (1-33). [Means for solving the problem]

[0010] In the first aspect, a GLP-1 / GLP-2 dual agonist represented by the following formula, for use in methods of reducing or preventing weight gain, reducing food intake, reducing appetite, promoting weight loss, or treating obesity, morbid obesity, obesity-related gallbladder disease, or obesity-induced sleep apnea: R 1 -X * -UR 2 [In the formula, R 1 is hydrogen (Hy), C 1-4 Alkyl (e.g., methyl), acetyl, formyl, benzoyl, or trifluoroacetyl, R 2 It is NH2 or OH, X * This is the peptide of formula I: H-X2-EG-X5-F-X7-X8-E-X10-X11-TIL-X15-X16-X17-A-X19-X20-X21-FI-X24-WL-X27-X28-X29-KIT-X33(I) (Sequence number 1) And, During the ceremony, X2 is either Aib or G. X5 is either T or S. X7 is T or S, X8 is S, E, or D, X10 is L, M, V, or Ψ, X11 is A, N, or S, X15 is D or E, X16 is G, E, A, or Ψ, X17 is Q, E, K, L, or Ψ, X19 is A, V, or S, X20 is R, K, or Ψ, X21 is D, L, or E, X24 is A, N, or S, X27 is I, Q, K, H, or Y, X28 is Q, E, A, H, Y, L, K, R, or S, X29 is H, Y, K, or Q, X33 is D or E, U is absent or is a sequence of 1 to 15 residues independently selected from K, k, E, A, T, I, L, and Ψ, This molecule contains only one Ψ, where Ψ is a residue of K, k, R, Orn, Dap, or Dab conjugated with a substituent having a side chain of formula Z 1 - or Z 1 -Z 2 - and [wherein, Z 1 - is CH3-(CH2) 10-22 -(CO)- or HOOC-(CH2) 10-22 -(CO)-, -Z 2 - is -Z S1 -, -Z S1 -Z S2 -, -Z S2 -Z S1 -, -Z S2 -, -Z S3 -, -Z S1 Z S3 -, -Z S2 Z S3 -, -Z S3 Z S1 -, -Z S3 ZS2 -, -Z S1 Z S2 Z S3 -, -Z S1 Z S3 Z S2 -, -Z S2 Z S1 Z S3 -, -Z S2 Z S3 Z S1 -, -Z S3 Z S1 Z S2 -, -Z S3 Z S2 Z S1 -, -Z S2 Z S3 Z S2 - Selected from, in the formula, Z S1 isoGlu, β-Ala, isoLys, or 4-aminobutanoyl, Z S2 is -(Peg3) m -where m is 1, 2, or 3, -Z S3 - is a peptide sequence of 1 to 6 amino acid units independently selected from the group consisting of A, L, S, T, Y, Q, D, E, K, k, R, H, F, and G. At least one of X5 and X7 is T] A dual agonist or a pharmaceutically acceptable salt or solvate thereof is provided, comprising the step of administering the dual agonist to a patient in a dose of about 0.1 mg to about 10.0 mg.

[0011] The peptide X formula provided here * The various amino acid positions within the molecule are numbered according to their linear positions in the amino acid chain, from the N-terminus to the C-terminus.

[0012] In this context, β-Ala and 3-aminopropanoyl are used interchangeably.

[0013] Dual agonists with aspartic acid (Asp, D) at position 3 and glycine (Gly) at position 4 can be very potent agonists for GLP-1 and GLP-2 receptors. However, this substitution combination results in unstable compounds that may not be suitable for long-term storage in aqueous solutions. While we do not wish to be bound by theory, it is thought that the Asp at position 3 may isomerize to iso-Asp via a cyclic intermediate formed between the carboxylic acid functional group of its side chain and the main chain nitrogen atom of the residue at position 4.

[0014] This study found that molecules with glutamic acid (Glu, E) at position 3 instead of Asp are far less sensitive to such reactions and are therefore considerably more stable when stored in aqueous solution. However, substitution of Asp at position 3 with Glu in molecules with lipophilic substituents in the central part of the peptide (e.g., positions 16 and 17 or nearby) tends to reduce the potency of one or both GLP-2 and GLP-1 receptors, despite the presence of Glu at position 3 in the native GLP-1 molecule. It appears that some or all of the lost potency can be compensated for by simultaneously incorporating Thr residues at one or both positions 5 and 7. Further improvements in potency are also thought to be provided by incorporating His(H), Tyr(Y), Lys(K), or Gln(Q) at position 29, instead of the Gly(G) and Thr(T) residues present in wild-type human GLP-1 and 2, respectively.

[0015] In some embodiments of formula I, X2 is either Aib or G. X5 is either T or S. X7 is either T or S. X8 is S, X10 is L or Ψ, X11 is either A or S. X15 is either D or E. X16 is G, E, A, or Ψ, X17 is Q, E, K, L, or Ψ. X19 is either A or S. X20 is R or Ψ, X21 is D, L, or E. X24 is A, X27 is I, Q, K, or Y. X28 is Q, E, A, H, Y, L, K, R, or S. X29 is H, Y, or Q. X33 is either D or E.

[0016] If Ψ is not in X16 or X17, it may be desirable that X16 be E and X17 be Q.

[0017] In some embodiments, X11 is A and X15 is D. In other embodiments, X11 is S and X15 is E. In further embodiments, X11 is A and X15 is E.

[0018] In some embodiments, X27 is I.

[0019] In some embodiments, X29 is H. In certain embodiments of these embodiments, X28 is A and X29 is H, or X28 is E and X29 is H.

[0020] In some embodiments, X29 may be Q and X27 may be Q.

[0021] In some embodiments, the residues X27-X29 have sequences selected from the following: IQH, IEH, IAH, IHH, IYH, ILH, IKH, IRH, ISH, QQH, YQH, KQH, IQQ, IQY, IQT, and IAY.

[0022] In some embodiments, X * This is the peptide of formula II: H-X2-EG-X5-F-X7-SELATILD-X16-X17-AAR-X21-FIAWLI-X28-X29-KITD(II) (SEQ ID NO: 2) [In the formula, X2 is either Aib or G. X5 is either T or S. X7 is either T or S. X16 is G or Ψ, X17 is Q, E, K, L, or Ψ. X21 is either D or L. X28 is Q, E, A, H, Y, L, K, R, or S. X29 is H, Y, or Q.

[0023] In some embodiments of Formula I or Formula II, X16 is Ψ and X17 is Q, E, K, or L. For example, X17 may be Q, or X17 may be selected from E, K, and L. In other embodiments, X16 is G and X17 is Ψ.

[0024] In some cases, it is preferable for X21 to be D.

[0025] X28 can be selected from Q, E, and A, for example, it may be Q or E. In some combinations of residues, Q may be preferred. E may be preferred in other combinations, including, but not limited to, when X16 is G and X17 is Ψ. Alternatively, X28 can be selected from A, H, Y, L, K, R, and S.

[0026] X * This could be a peptide of formula III: H[Aib]EG-X5-F-X7-SE-X10-ATILD-X16-X17-AA-X20-X21-FIAWLI-X28-X29-KITD(III) (SEQ ID NO: 3) [In the formula, X5 is either T or S. X7 is either T or S. X10 is L or Ψ, X16 is G, E, A, or Ψ, X17 is Q, E, K, L, or Ψ. X20 is R or Ψ, X21 is either D or L. X28 is E, A, or Q. X29 is H, Y, or Q. At least one of X5 and X7 is T.

[0027] X * This could be the peptide of formula IV: H[Aib]EG-X5-F-X7-SELATILD-X16-X17-AAR-X21-FIAWLI-X28-X29-KITD(IV) (SEQ ID NO: 4) [In the formula, X5 is either T or S. X7 is either T or S. X16 is G or Ψ, X17 is E, K, L, or Ψ. X21 is either D or L. X28 is either E or A. X29 is H, Y, or Q. At least one of X5 and X7 is T.

[0028] In some embodiments of any of the formulas I to IV, X16 is Ψ and X17 is E, K, or L.

[0029] In other embodiments of equations I to IV, X16 is G and X17 is Ψ.

[0030] In either case, the following combinations of residues may also be included: X21 is D, and X28 is E. X21 is D, and X28 is A. X21 is L, and X28 is E. X21 is L, and X28 is A.

[0031] X * This could be the peptide of formula V: H[Aib]EG-X5-F-X7-SELATILD-Ψ-QAARDFIAWLI-X28-X29-KITD(V)(Sequence No. 5) [In the formula, X5 is either T or S. X7 is either T or S. X28 is Q, E, A, H, Y, L, K, R, or S, for example, Q, E, A, H, Y, or L. X29 is H, Y, or Q. At least one of X5 and X7 is T.

[0032] In some embodiments of Formula III, X28 is Q or E. In other embodiments, X28 is A, H, Y, L, K, R, or S, for example, A, H, Y, or L.

[0033] In any of the above formulas or embodiments, the double agonist contains one of the following combinations of residues: X5 is S, X7 is T, X5 is T, and X7 is S. X5 is T, and X7 is T.

[0034] It may be preferable that X5 is S and X7 is T, or that X5 is T and X7 is T.

[0035] In any of the above formulas or embodiments, it may be desirable that X29 be H.

[0036] In some embodiments, Ψ has a side chain with substituent Z. 1 - or Z 1 -Z 2 - This is a Lys residue that is conjugated with

[0037] In some embodiments, Z 1 -, alone or -Z 2 -In combination with these, they are dodecanoyl, tetradecanoyl, hexadecanoyl, octadecanoyl, or eicosaenoyl.

[0038] In some embodiments, Z 1 -, alone or -Z 2 - Combined with the following: 13-Carboxytridecanoyl, i.e., HOOC-(CH2) 12 -(CO)-; 15-Carboxypentadecanoyl, i.e., HOOC-(CH2) 14 -(CO)-; 17-Carboxyheptadecanoyl, i.e., HOOC-(CH2) 16 -(CO)-; 19-Carboxynonadecanoyl, i.e., HOOC-(CH2) 18 -(CO)-; or 21-Carboxyhexenoyl, i.e., HOOC-(CH2) 20 -(CO)-

[0039] In some embodiments, Z 2 It does not exist.

[0040] In some embodiments, Z 2 is, Z S1 Use alone or Z S2 and / or Z S3 Includes in combination with.

[0041] In such embodiments, -Z S1 - is isoGlu, β-Ala, isoLys, or 4-aminobutanoyl, -Z S2 - is -(Peg3) if it exists. m -where m is 1, 2, or 3, -Z S3- is a peptide sequence of 1 to 6 amino acid units independently selected from the group consisting of A, L, S, T, Y, Q, D, E, K, k, R, H, F, and G, for example, the peptide sequence KEK.

[0042] Z 2 is of the formula -Z S1 -Z S3 -Z S2 - and may have [where Z S1 is bonded to Z 1 and Z S2 is bonded to the side chain of the amino acid component of Ψ].

[0043] Thus, in some embodiments, -Z 2 - is the following: isoGlu(Peg3) 0-3 , β-Ala(Peg3) 0-3 , isoLys(Peg3) 0-3 , or 4-aminobutanoyl(Peg3) 0-3 ,

[0044] In a further embodiment, -Z 2 - is isoGlu-KEK-(Peg3) 0-3 (SEQ ID NO: 6).

[0045] Substituent Z 1 -Z 2 - Specific examples are described below. In some embodiments, Z 1 -Z 2 - is [17-carboxy-heptadecanoyl]-isoGlu. For example, Ψ can be K([17-carboxy-heptadecanoyl]-isoGlu). In some embodiments, Z 1 -Z 2 - is the following: [17-carboxy-heptadecanoyl]-isoGlu-KEK-Peg3-; [17-carboxy-heptadecanoyl]-isoGlu-Peg3-; [19-carboxy-nonadecanoyl]-isoGlu-; [19-carboxy-nonadecanoyl]-isoGlu-KEK-; [19-Carboxy-nonadecanoyl]-isoGlu-KEK-Peg3-; [19-Carboxy-nonadecanoyl]-isoGlu-KEK-Peg3-Peg3-; [19-carboxy-nonadecanoyl]-isoGlu-Peg3-Peg3-; [19-carboxy-nonadecanoyl]-isoLys-Peg3-Peg3-Peg3-; [Hexadecanoyl]-βAla-; [Hexadecanoyl]-isoGlu-; or Octadecanoil.

[0046] For example, Ψ could be: K([17-carboxyheptadecanoyl]-isoGlu-KEK-Peg3); K([17-carboxyheptadecanoyl]-isoGlu-Peg3); K([19-carboxy-nonadecanoyl]-isoGlu); K([19-carboxy-nonadecanoyl]-isoGlu-KEK); K([19-carboxy-nonadecanoyl]-isoGlu-KEK-Peg3); K([19-carboxy-nonadecanoyl]-isoGlu-KEK-Peg3-Peg3); K([19-carboxy-nonadecanoyl]-isoGlu-Peg3-Peg3); K([19-carboxy-nonadecanoyl]-isoLys-Peg3-Peg3-Peg3); K([Hexadecanoyl]-βAla-; K([Hexadecanoyl]-isoGlu); or K (Octadecanoyl).

[0047] If present, U represents a peptide sequence of 1 to 15 residues independently selected from K (i.e., L-lysine), k (i.e., D-lysine), E (Glu), A (Ala), T (Thr), I (Ile), L (Leu), and Ψ. For example, U may be the length of 1 to 10 amino acids, 1 to 7 amino acids, 3 to 7 amino acids, 1 to 6 amino acids, or 3 to 6 amino acids.

[0048] Typically, U comprises at least one charged amino acid (K, k, or E) and preferably two or more charged amino acids. In some embodiments, it comprises at least two positively charged amino acids (K or k), or at least one positively charged amino acid (K or k) and at least one uncharged amino acid (E). In some embodiments, all amino acid residues of U (except Ψ, if present) are charged. For example, U may be a chain of alternating positively and uncharged amino acids.

[0049] In certain embodiments, U comprises a residue selected from K, k, E, and Ψ only.

[0050] In certain embodiments, U comprises a residue selected from K, k, and Ψ only.

[0051] If U contains only lysine residues (regardless of whether they are K or k), then all residues may have an L-conformation, or all may have a D-conformation. For example, K 1~15 , K 1~10 , and K 1~7 For example, K3, K4, K5, K6, and K7, especially K5 and K6. Further examples include k 1~15 , k 1~10 , and k 1~7 Examples include k3, k4, k5, k6, and k7, particularly k5 and k6.

[0052] Further examples of peptide sequence U include KEK, EKEKEK (SEQ ID NO: 7), EkEkEk (SEQ ID NO: 8), AKAAEK (SEQ ID NO: 9), AKEKEK (SEQ ID NO: 10), and ATILEK (SEQ ID NO: 11).

[0053] In either case, one of these residues can be replaced with Ψ. If sequence U contains the residue Ψ, it may be desirable that the C-terminal residue of U be Ψ. Therefore, a further example of sequence U is K 1~14 -Ψ, K 1~9 -Ψ, and K 1~6 -Ψ, for example, K2-Ψ, K3-Ψ, K4-Ψ, K5-Ψ, and K6-Ψ, especially K4-Ψ and K5-Ψ. Further examples include k 1~14 -Ψ,k 1~9 -Ψ, and k 1~6 -Ψ, for example, k2-Ψ, k3-Ψ, k4-Ψ, k5-Ψ, and k6-Ψ, especially k4-Ψ and k5-Ψ. Further examples include KEΨ, EKEKEΨ (sequence number 12), EkEkEΨ (sequence number 13), AKAAEΨ (sequence number 14), AKEKEΨ (sequence number 15), and ATILEΨ (sequence number 16).

[0054] In some embodiments, U is absent.

[0055] In some embodiments, R 1 is Hy, and / or R 2 It is OH.

[0056] Peptide X * or Peptide X * -U may have the following sequence: H[Aib]EGTFSSELATILDΨEAARDFIAWLIEHKITD (Sequence ID 17); H[Aib]EGSFTSELATILDΨEAARDFIAWLIEHKITD (Sequence ID 18); H[Aib]EGTFTSELATILDΨEAARDFIAWLIEHKITD (Sequence ID 19); H[Aib]EGTFSSELATILDΨKAARDFIAWLIEHKITD (Sequence ID 20); H[Aib]EGSFTSELATILDΨKAARDFIAWLIEHKITD (Sequence No. 21); H[Aib]EGTFTSELATILDΨKAARDFIAWLIEHKITD (Sequence code 22); H[Aib]EGTFSSELATILDGΨAARDFIAWLIEHKITD (Sequence No. 23); H[Aib]EGSFTSELATILDGΨAARDFIAWLIEHKITD (Sequence code 24); H[Aib]EGTFTSELATILDGΨAARDFIAWLIEHKITD (Sequence ID 25); H[Aib]EGTFSSELATILDΨLAARDFIAWLIEHKITD (Sequence No. 26); H[Aib]EGSFTSELATILDΨLAARDFIAWLIEHKITD (Sequence No. 27); H[Aib]EGTFTSELATILDΨLAARDFIAWLIEHKITD (Sequence No. 28); H[Aib]EGTFSSELATILDΨLAARDFIAWLIAHKITD (Sequence No. 29); H[Aib]EGSFTSELATILDΨLAARDFIAWLIAHKITD (Sequence ID 30); H[Aib]EGTFTSELATILDΨLAARDFIAWLIAHKITD (Sequence No. 31); H[Aib]EGTFTSELATILDΨEAARLFIAWLIEHKITD (Sequence ID 32); H[Aib]EGTFSSELATILDΨQAARDFIAWLIQHKITD (Sequence ID 33); H[Aib]EGSFTSELATILDΨQAARDFIAWLIQHKITD (Sequence ID 34); H[Aib]EGTFTSELATILDΨQAARDFIAWLIQHKITD (Sequence ID 35); H[Aib]EGTFSSELATILDΨQAARDFIAWLIEHKITD (Sequence ID 36); H[Aib]EGTFSSELATILDΨQAARDFIAWLIAHKITD (Sequence No. 37); H[Aib]EGSFTSELATILDΨQAARDFIAWLIAHKITD (Sequence ID 38); H[Aib]EGTFTSELATILDΨQAARDFIAWLIAHKITD (Sequence ID 39); H[Aib]EGSFTSELATILDΨQAARDFIAWLIEHKITD (Sequence ID 40); H[Aib]EGTFTSELATILDΨQAARDFIAWLIEHKITD (Sequence ID 41); H[Aib]EGSFTSELATILDΨQAARDFIAWLIHHKITD (Sequence code 42); H[Aib]EGSFTSELATILDΨQAARDFIAWLIYHKITD (Sequence ID 43); H[Aib]EGSFTSELATILDΨQAARDFIAWLILHKITD (Sequence ID 44); H[Aib]EGSFTSELATILDΨQAARDFIAWLIKHKITD (Sequence ID 45); H[Aib]EGSFTSELATILDΨQAARDFIAWLIRHKITD (Sequence ID 46); H[Aib]EGSFTSELATILDΨQAARDFIAWLISHKITD (Sequence No. 47); H[Aib]EGSFTSELATILDΨQAARDFIAWLQQHKITD (Sequence ID 48); H[Aib]EGSFTSELATILDΨQAARDFIAWLYQHKITD (Sequence ID 49); H[Aib]EGSFTSELATILDΨQAARDFIAWLKQHKITD (Sequence ID 50); H[Aib]EGSFTSELATILDΨQAARDFIAWLIQQKITD (Sequence ID 51); H[Aib]EGSFTSELATILDΨQAARDFIAWLIQYKITD (Sequence ID 52); H[Aib]EGTFSSELSTILEΨQASREFIAWLIAYKITE (Sequence ID 53); H[Aib]EGTFSSELATILDEQAARDFIAWLIAHKITDkkkkkΨ (Sequence ID 54); H[Aib]EGTFTSELATILDEQAARDFIAWLIAHKITDkkkkkΨ (Sequence ID 55); H[Aib]EGSFTSELATILDEQAARDFIAWLIEHKITDkkkkkΨ (Sequence code 56); H[Aib]EGSFTSEΨATILDEQAARDFIAWLIEHKITD (Sequence ID 57); H[Aib]EGSFTSELATILEGΨAARDFIAWLIEHKITD (Sequence ID 58); H[Aib]EGSFTSELATILDEQAAΨDFIAWLIEHKITD (Sequence ID 59); H[Aib]EGTFTSELATILDEQAAΨDFIAWLIEHKITD (Sequence ID 60); H[Aib]EGTFTSEψATILDEQAARDFIAWLIEHKITD (Sequence ID 61); H[Aib]EGSFTSELATILDAψAARDFIAWLIEHKITD (Sequence ID 62); or H[Aib]EGSFTSELATILDAKAAψDFIAWLIEHKITD (Sequence ID 63).

[0057] Peptide X * or Peptide X * -U may have the following sequence: H[Aib]EGTFSSELATILD[K*]EAARDFIAWLIEHKITD (Sequence ID 64); H[Aib]EGSFTSELATILD[K*]EAARDFIAWLIEHKITD (Sequence ID 65); H[Aib]EGTFTSELATILD[K*]EAARDFIAWLIEHKITD (Sequence code 66); H[Aib]EGTFSSELATILD[K*]KAARDFIAWLIEHKITD (Sequence code 67); H[Aib]EGSFTSELATILD[K*]KAARDFIAWLIEHKITD (Sequence ID 68); H[Aib]EGTFTSELATILD[K*]KAARDFIAWLIEHKITD (Sequence ID 69); H[Aib]EGTFSSELATILDG[K*]AARDFIAWLIEHKITD (Sequence ID 70); H[Aib]EGSFTSELATILDG[K*]AARDFIAWLIEHKITD (Sequence ID 71); H[Aib]EGTFTSELATILDG[K*]AARDFIAWLIEHKITD (Sequence ID 72); H[Aib]EGTFSSELATILD[K*]LAARDFIAWLIEHKITD (Sequence ID 73); H[Aib]EGSFTSELATILD[K*]LAARDFIAWLIEHKITD (Sequence code 74); H[Aib]EGTFTSELATILD[K*]LAARDFIAWLIEHKITD (Sequence ID 75); H[Aib]EGTFSSELATILD[K*]LAARDFIAWLIAHKITD (Sequence code 76); H[Aib]EGSFTSELATILD[K*]LAARDFIAWLIAHKITD (Sequence code 77); H[Aib]EGTFTSELATILD[K*]LAARDFIAWLIAHKITD (Sequence ID 78); H[Aib]EGTFTSELATILD[K*]EAARLFIAWLIEHKITD (Sequence ID 79); H[Aib]EGTFSSELATILD[K*]QAARDFIAWLIQHKITD (Sequence ID 80); H[Aib]EGSFTSELATILD[K*]QAARDFIAWLIQHKITD (Sequence ID 81); H[Aib]EGTFTSELATILD[K*]QAARDFIAWLIQHKITD (Sequence ID 82); H[Aib]EGTFSSELATILD[K*]QAARDFIAWLIEHKITD (Sequence ID 83); H[Aib]EGTFSSELATILD[K*]QAARDFIAWLIAHKITD (Sequence ID 84); H[Aib]EGSFTSELATILD[K*]QAARDFIAWLIAHKITD (Sequence ID 85); H[Aib]EGTFTSELATILD[K*]QAARDFIAWLIAHKITD (Sequence ID 86); H[Aib]EGSFTSELATILD[K*]QAARDFIAWLIEHKITD (Sequence code 87); H[Aib]EGTFTSELATILD[K*]QAARDFIAWLIEHKITD (Sequence ID 88); H[Aib]EGSFTSELATILD[K*]QAARDFIAWLIHHKITD (Sequence ID 89); H[Aib]EGSFTSELATILD[K*]QAARDFIAWLIYHKITD (Sequence ID 90); H[Aib]EGSFTSELATILD[K*]QAARDFIAWLILHKITD (Sequence ID 91); H[Aib]EGSFTSELATILD[K*]QAARDFIAWLIKHKITD (Sequence ID 92); H[Aib]EGSFTSELATILD[K*]QAARDFIAWLIRHKITD (Sequence ID 93); H[Aib]EGSFTSELATILD[K*]QAARDFIAWLISHKITD (Sequence ID 94); H[Aib]EGSFTSELATILD[K*]QAARDFIAWLQQHKITD (Sequence ID 95); H[Aib]EGSFTSELATILD[K*]QAARDFIAWLYQHKITD (Sequence code 96); H[Aib]EGSFTSELATILD[K*]QAARDFIAWLKQHKITD (Sequence code 97); H[Aib]EGSFTSELATILD[K*]QAARDFIAWLIQQKITD (Sequence ID 98); H[Aib]EGSFTSELATILD[K*]QAARDFIAWLIQYKITD (Sequence ID 99); H[Aib]EGTFSSELSTILE[K*]QASREFIAWLIAYKITE (Sequence ID 100); H[Aib]EGTFSSELATILDEQAARDFIAWLIAHKITDkkkkk[k*] (Sequence ID 101); H[Aib]EGTFTSELATILDEQAARDFIAWLIAHKITDkkkkk[k*] (Sequence ID 102); H[Aib]EGSFTSELATILDEQAARDFIAWLIEHKITDkkkkk[k*] (Sequence ID 103); H[Aib]EGSFTSE[K*]ATILDEQAARDFIAWLIEHKITD (Sequence ID 104); H[Aib]EGSFTSELATILEG[K*]AARDFIAWLIEHKITD (Sequence ID 105); H[Aib]EGSFTSELATILDEQAA[K*]DFIAWLIEHKITD (Sequence ID 106); H[Aib]EGTFTSELATILDEQAA[K*]DFIAWLIEHKITD (Sequence ID 107); H[Aib]EGTFTSE[K*]ATILDEQAARDFIAWLIEHKITD (Sequence ID 108); H[Aib]EGSFTSELATILDA[K*]AARDFIAWLIEHKITD (Sequence ID 109); or H[Aib]EGSFTSELATILDAKAA[K*]DFIAWLIEHKITD (Sequence ID 110); [In the formula, K * or k * Each of these has a side chain with substituent Z. 1 - or Z 1 Z2 - Indicates an L or D lysine residue that is conjugated with [

[0058] For example, peptide X * or Peptide X * -U may have the following sequence: H[Aib]EGTFSSELATILD[K([17-carboxy-heptadecanoyl]-isoGlu)]EAARDFIAWLIEHKITD (Sequence ID 111); H[Aib]EGSFTSELATILD[K([17-carboxy-heptadecanoyl]-isoGlu)]EAARDFIAWLIEHKITD (Sequence ID 112); H[Aib]EGTFTSELATILD[K([17-carboxy-heptadecanoyl]-isoGlu)]EAARDFIAWLIEHKITD (Sequence ID 113); H[Aib]EGTFSSELATILD[K([17-carboxy-heptadecanoyl]-isoGlu)]KAARDFIAWLIEHKITD (Sequence ID 114); H[Aib]EGSFTSELATILD[K([17-carboxy-heptadecanoyl]-isoGlu)]KAARDFIAWLIEHKITD (Sequence ID 115); H[Aib]EGTFTSELATILD[K([17-carboxy-heptadecanoyl]-isoGlu)]KAARDFIAWLIEHKITD (Sequence ID 116); H[Aib]EGTFSSELATILDG[K([17-carboxy-heptadecanoyl]-isoGlu)]AARDFIAWLIEHKITD (Sequence ID 117); H[Aib]EGSFTSELATILDG[K([17-carboxy-heptadecanoyl]-isoGlu)]AARDFIAWLIEHKITD (Sequence ID 118); H[Aib]EGTFTSELATILDG[K([17-carboxy-heptadecanoyl]-isoGlu)]AARDFIAWLIEHKITD (Sequence ID 119); H[Aib]EGTFSSELATILD[K([17-carboxy-heptadecanoyl]-isoGlu)]LAARDFIAWLIEHKITD (Sequence ID 120); H[Aib]EGSFTSELATILD[K([17-carboxy-heptadecanoyl]-isoGlu)]LAARDFIAWLIEHKITD (Sequence ID 121); H[Aib]EGTFTSELATILD[K([17-carboxy-heptadecanoyl]-isoGlu)]LAARDFIAWLIEHKITD (Sequence ID 122); H[Aib]EGTFSSELATILD[K([17-carboxy-heptadecanoyl]-isoGlu)]LAARDFIAWLIAHKITD (Sequence ID 123); H[Aib]EGSFTSELATILD[K([17-carboxy-heptadecanoyl]-isoGlu)]LAARDFIAWLIAHKITD (Sequence ID 124); H[Aib]EGTFTSELATILD[K([17-carboxy-heptadecanoyl]-isoGlu)]LAARDFIAWLIAHKITD (Sequence ID 125); H[Aib]EGTFTSELATILD[K([17-carboxy-heptadecanoyl]-isoGlu)]EAARLFIAWLIEHKITD (Sequence ID 126); H[Aib]EGTFSSELATILD[K([17-carboxy-heptadecanoyl]-isoGlu)]QAARDFIAWLIQHKITD (Sequence ID 127); H[Aib]EGSFTSELATILD[K([17-carboxy-heptadecanoyl]-isoGlu)]QAARDFIAWLIQHKITD (Sequence ID 128); H[Aib]EGTFTSELATILD[K([17-carboxy-heptadecanoyl]-isoGlu)]QAARDFIAWLIQHKITD (Sequence ID 129); H[Aib]EGTFSSELATILD[K([17-carboxy-heptadecanoyl]-isoGlu)]QAARDFIAWLIEHKITD (Sequence ID 130); H[Aib]EGTFSSELATILD[K([17-carboxy-heptadecanoyl]-isoGlu)]QAARDFIAWLIAHKITD (Sequence ID 131); H[Aib]EGSFTSELATILD[K([17-carboxy-heptadecanoyl]-isoGlu)]QAARDFIAWLIAHKITD (Sequence ID 132); H[Aib]EGTFTSELATILD[K([17-carboxy-heptadecanoyl]-isoGlu)]QAARDFIAWLIAHKITD (Sequence ID 133); H[Aib]EGSFTSELATILD[K([17-carboxy-heptadecanoyl]-isoGlu)]QAARDFIAWLIEHKITD (Sequence ID 134); H[Aib]EGTFTSELATILD[K([17-carboxy-heptadecanoyl]-isoGlu)]QAARDFIAWLIEHKITD (Sequence ID 135); H[Aib]EGSFTSELATILD[K([17-carboxy-heptadecanoyl]-isoGlu)]QAARDFIAWLIHHKITD (Sequence ID 136); H[Aib]EGSFTSELATILD[K([17-carboxy-heptadecanoyl]-isoGlu)]QAARDFIAWLIYHKITD (Sequence ID 137); H[Aib]EGSFTSELATILD[K([17-carboxy-heptadecanoyl]-isoGlu)]QAARDFIAWLILHKITD (Sequence ID 138); H[Aib]EGSFTSELATILD[K([17-carboxy-heptadecanoyl]-isoGlu)]QAARDFIAWLIKHKITD (Sequence ID 139); H[Aib]EGSFTSELATILD[K([17-carboxy-heptadecanoyl]-isoGlu)]QAARDFIAWLIRHKITD (Sequence ID 140); H[Aib]EGSFTSELATILD[K([17-carboxy-heptadecanoyl]-isoGlu)]QAARDFIAWLISHKITD (Sequence ID 141); H[Aib]EGSFTSELATILD[K([Hexadecanoyl]-βAla)]QAARDFIAWLQQHKITD (Sequence ID 142); H[Aib]EGSFTSELATILD[K([17-carboxy-heptadecanoyl]iso-Glu-Peg3)]QAARDFIAWLYQHKITD (Sequence ID 143); H[Aib]EGSFTSELATILD[K([19-carboxy-nonadecanoyl]iso-Glu-Peg3-Peg3)]QAARDFIAWLKQHKITD (Sequence ID 144); H[Aib]EGSFTSELATILD[K([19-carboxy-nonadecanoyl]iso-Lys-Peg3-Peg3-Peg3)]QAARDFIAWLIQQKITD (Sequence ID 145); H[Aib]EGSFTSELATILD[K(octadecanoyl)]QAARDFIAWLIQYKITD (Sequence ID 146); H[Aib]EGTFSSELSTILE[K(Hexadecanoyl-isoGlu)]QASREFIAWLIAYKITE (Sequence ID 147); H[Aib]EGTFSSELATILDEQAARDFIAWLIAHKITDkkkkkk([17-carboxyheptadecanoyl]-isoGlu)] (Sequence ID 148); H[Aib]EGTFTSELATILDEQAARDFIAWLIAHKITDkkkkkk([17-carboxy-heptadecanoyl]-isoGlu)] (Sequence ID 149); H[Aib]EGSFTSELATILDEQAARDFIAWLIEHKITDkkkkkk([17-carboxy-heptadecanoyl]-isoGlu)] (Sequence ID 150); H[Aib]EGTFTSELATILD[K([19-carboxy-nonadecanoyl]-isoGlu)]QAARDFIAWLIQHKITD (Sequence ID 151); H[Aib]EGSFTSE[K([19-carboxy-nonadecanoyl]iso-Glu-Peg3-Peg3)]ATILDEQAARDFIAWLIEHKITD (Sequence ID 152); H[Aib]EGSFTSELATILD[K([19-carboxy-nonadecanoyl]iso-Glu-Peg3-Peg3)]KAARDFIAWLIEHKITD (Sequence ID 153); H[Aib]EGSFTSELATILEG[K([19-carboxy-nonadecanoyl]iso-Glu-Peg3-Peg3)]AARDFIAWLIEHKITD (Sequence ID 154); H[Aib]EGSFTSELATILDEQAA[K([19-carboxy-nonadecanoyl]iso-Glu-Peg3-Peg3)]DFIAWLIEHKITD (Sequence ID 155); H[Aib]EGTFTSELATILDEQAA[K([19-carboxy-nonadecanoyl]iso-Glu-Peg3-Peg3)]DFIAWLIEHKITD (Sequence ID 156); H[Aib]EGTFSSELATILD[K([17-carboxy-heptadecanoyl]-isoGlu-KEK-Peg3)]QAARDFIAWLIQHKITD (Sequence ID 157); H[Aib]EGTFSSELATILD[K([19-carboxy-nonadecanoyl]-isoGlu-KEK-Peg3)]QAARDFIAWLIQHKITD (Sequence ID 158); H[Aib]EGTFSSELATILD[K([17-carboxy-heptadecanoyl]-isoGlu-KEK-Peg3)]QAARDFIAWLIEHKITD (Sequence ID 159); H[Aib]EGTFSSELATILD[K([19-carboxy-nonadecanoyl]-isoGlu-KEK-Peg3)]QAARDFIAWLIEHKITD (Sequence ID 160); H[Aib]EGTFTSELATILD[K([19-carboxy-nonadecanoyl]-isoGlu-KEK)]QAARDFIAWLIQHKITD (Sequence ID 161); H[Aib]EGTFTSELATILD[K([19-carboxy-nonadecanoyl]-isoGlu-KEK-Peg3)]QAARDFIAWLIQHKITD (Sequence ID 162); H[Aib]EGSFTSE[K([19-carboxy-nonadecanoyl]-isoGlu-KEK-Peg3)]ATILDEQAARDFIAWLIEHKITD (Sequence ID 163); H[Aib]EGTFTSE[K([19-carboxy-nonadecanoyl]-isoGlu-KEK-Peg3)]ATILDEQAARDFIAWLIEHKITD (Sequence ID 164); H[Aib]EGSFTSE[K([19-carboxy-nonadecanoyl]iso-Glu-KEK-Peg3-Peg3)]ATILDEQAARDFIAWLIEHKITD (Sequence ID 165); H[Aib]EGTFTSELATILD[K([19-carboxy-nonadecanoyl]-isoGlu-KEK-Peg3)]QAARDFIAWLIEHKITD (Sequence ID 166); H[Aib]EGSFTSELATILD[K([19-carboxy-nonadecanoyl]-isoGlu-KEK-Peg3)]QAARDFIAWLIEHKITD (Sequence ID 167); H[Aib]EGSFTSELATILD[K([19-carboxy-nonadecanoyl]-isoGlu-KEK-Peg3)]QAARDFIAWLIAHKITD (Sequence ID 168); H[Aib]EGSFTSELATILD[K([19-carboxy-nonadecanoyl]-isoGlu-KEK-Peg3)]KAARDFIAWLIEHKITD (Sequence ID 169); H[Aib]EGSFTSELATILD[K([19-carboxy-nonadecanoyl]iso-Glu-KEK-Peg3-Peg3)]QAARDFIAWLIEHKITD (Sequence ID 170); H[Aib]EGSFTSELATILEG[K([19-carboxy-nonadecanoyl]-isoGlu-KEK-Peg3)]AARDFIAWLIEHKITD (Sequence ID 171); H[Aib]EGSFTSELATILDA[K([19-carboxy-nonadecanoyl]-isoGlu-KEK-Peg3)]AARDFIAWLIEHKITD (Sequence ID 172); H[Aib]EGSFTSELATILDA[K([19-carboxy-nonadecanoyl]iso-Glu-KEK-Peg3-Peg3)]AARDFIAWLIEHKITD (Sequence ID 173); H[Aib]EGSFTSELATILDEQAA[K([19-carboxy-nonadecanoyl]-isoGlu-KEK-Peg3)]DFIAWLIEHKITD (Sequence ID 174); H[Aib]EGTFTSELATILDEQAA[K([19-carboxy-nonadecanoyl]-isoGlu-KEK-Peg3)]DFIAWLIEHKITD (Sequence ID 175); H[Aib]EGSFTSELATILDEQAA[K([19-carboxy-nonadecanoyl]iso-Glu-KEK-Peg3-Peg3)]DFIAWLIEHKITD (Sequence ID 176); H[Aib]EGTFTSELATILDEQAA[K([19-carboxy-nonadecanoyl]iso-Glu-KEK-Peg3-Peg3)]DFIAWLIEHKITD (Sequence ID 177); or H[Aib]EGSFTSELATILDAKAA[K([19-carboxy-nonadecanoyl]-isoGlu-KEK-Peg3)]DFIAWLIEHKITD (Sequence ID 178).

[0059] A dual agonist could be: Hy-H[Aib]EGTFSSELATILD[K([17-carboxy-heptadecanoyl]-isoGlu)]EAARDFIAWLIEHKITD-OH (Compound 1); Hy-H[Aib]EGSFTSELATILD[K([17-carboxy-heptadecanoyl]-isoGlu)]EAARDFIAWLIEHKITD-OH (Compound 2); Hy-H[Aib]EGTFTSELATILD[K([17-carboxy-heptadecanoyl]-isoGlu)]EAARDFIAWLIEHKITD-OH (Compound 3); Hy-H[Aib]EGTFSSELATILD[K([17-carboxy-heptadecanoyl]-isoGlu)]KAARDFIAWLIEHKITD-OH (Compound 4); Hy-H[Aib]EGSFTSELATILD[K([17-carboxy-heptadecanoyl]-isoGlu)]KAARDFIAWLIEHKITD-OH (Compound 5); Hy-H[Aib]EGTFTSELATILD[K([17-carboxy-heptadecanoyl]-isoGlu)]KAARDFIAWLIEHKITD-OH (Compound 6); Hy-H[Aib]EGTFSSELATILDG[K([17-carboxy-heptadecanoyl]-isoGlu)]AARDFIAWLIEHKITD-OH (Compound 7); Hy-H[Aib]EGSFTSELATILDG[K([17-carboxy-heptadecanoyl]-isoGlu)]AARDFIAWLIEHKITD-OH (Compound 8); Hy-H[Aib]EGTFTSELATILDG[K([17-carboxy-heptadecanoyl]-isoGlu)]AARDFIAWLIEHKITD-OH (Compound 9); Hy-H[Aib]EGTFSSELATILD[K([17-carboxy-heptadecanoyl]-isoGlu)]LAARDFIAWLIEHKITD-OH (Compound 10); Hy-H[Aib]EGSFTSELATILD[K([17-carboxy-heptadecanoyl]-isoGlu)]LAARDFIAWLIEHKITD-OH (Compound 11); Hy-H[Aib]EGTFTSELATILD[K([17-carboxy-heptadecanoyl]-isoGlu)]LAARDFIAWLIEHKITD-OH (Compound 12); Hy-H[Aib]EGTFSSELATILD[K([17-carboxy-heptadecanoyl]-isoGlu)]LAARDFIAWLIAHKITD-OH (Compound 13); Hy-H[Aib]EGSFTSELATILD[K([17-carboxy-heptadecanoyl]-isoGlu)]LAARDFIAWLIAHKITD-OH (Compound 14); Hy-H[Aib]EGTFTSELATILD[K([17-carboxy-heptadecanoyl]-isoGlu)]LAARDFIAWLIAHKITD-OH (Compound 15); Hy-H[Aib]EGTFTSELATILD[K([17-carboxy-heptadecanoyl]-isoGlu)]EAARLFIAWLIEHKITD-OH (Compound 16); Hy-H[Aib]EGTFSSELATILD[K([17-carboxy-heptadecanoyl]-isoGlu)]QAARDFIAWLIQHKITD-OH (Compound 17); Hy-H[Aib]EGSFTSELATILD[K([17-carboxy-heptadecanoyl]-isoGlu)]QAARDFIAWLIQHKITD-OH (Compound 18); Hy-H[Aib]EGTFTSELATILD[K([17-carboxy-heptadecanoyl]-isoGlu)]QAARDFIAWLIQHKITD-OH (Compound 19); Hy-H[Aib]EGTFSSELATILD[K([17-carboxy-heptadecanoyl]-isoGlu)]QAARDFIAWLIEHKITD-OH (Compound 20); Hy-H[Aib]EGTFSSELATILD[K([17-carboxy-heptadecanoyl]-isoGlu)]QAARDFIAWLIAHKITD-OH (Compound 21); Hy-H[Aib]EGSFTSELATILD[K([17-carboxy-heptadecanoyl]-isoGlu)]QAARDFIAWLIAHKITD-OH (Compound 22); Hy-H[Aib]EGTFTSELATILD[K([17-carboxy-heptadecanoyl]-isoGlu)]QAARDFIAWLIAHKITD-OH (Compound 23); Hy-H[Aib]EGSFTSELATILD[K([17-carboxy-heptadecanoyl]-isoGlu)]QAARDFIAWLIEHKITD-OH (Compound 24); Hy-H[Aib]EGTFTSELATILD[K([17-carboxy-heptadecanoyl]-isoGlu)]QAARDFIAWLIEHKITD-OH (Compound 25); Hy-H[Aib]EGSFTSELATILD[K([17-carboxy-heptadecanoyl]-isoGlu)]QAARDFIAWLIHHKITD-OH (Compound 26); Hy-H[Aib]EGSFTSELATILD[K([17-carboxy-heptadecanoyl]-isoGlu)]QAARDFIAWLIYHKITD-OH (Compound 27); Hy-H[Aib]EGSFTSELATILD[K([17-carboxy-heptadecanoyl]-isoGlu)]QAARDFIAWLILHKITD-OH (Compound 28); Hy-H[Aib]EGSFTSELATILD[K([17-carboxy-heptadecanoyl]-isoGlu)]QAARDFIAWLIKHKITD-OH (Compound 29); Hy-H[Aib]EGSFTSELATILD[K([17-carboxy-heptadecanoyl]-isoGlu)]QAARDFIAWLIRHKITD-OH (Compound 30); Hy-H[Aib]EGSFTSELATILD[K([17-carboxy-heptadecanoyl]-isoGlu)]QAARDFIAWLISHKITD-OH (Compound 31). Hy-H[Aib]EGSFTSELATILD[K([Hexadecanoyl]-βAla)]QAARDFIAWLQQHKITD-OH (Compound 32); Hy-H[Aib]EGSFTSELATILD[K([17-carboxyheptadecanoyl]iso-Glu-Peg3)]QAARDFIAWLYQHKITD-OH (Compound 33); Hy-H[Aib]EGSFTSELATILD[K([19-carboxy-nonadecanoyl]iso-Glu-Peg3-Peg3)]QAARDFIAWLKQHKITD-OH (Compound 34); Hy-H[Aib]EGSFTSELATILD[K([19-carboxy-nonadecanoyl]iso-Lys-Peg3-Peg3-Peg3)]QAARDFIAWLIQQKITD-OH (Compound 35); Hy-H[Aib]EGSFTSELATILD[K(octadecanoyl)]QAARDFIAWLIQYKITD-OH (Compound 36); Hy-H[Aib]EGTFSSELSTILE[K(Hexadecanoyl-isoGlu)]QASREFIAWLIAYKITE-OH (Compound 37); Hy-H[Aib]EGTFSSELATILDEQAARDFIAWLIAHKITDkkkkkk([17-carboxyheptadecanoyl]-isoGlu)]-[NH2] (Compound 38); Hy-H[Aib]EGTFTSELATILDEQAARDFIAWLIAHKITDkkkkkk([17-carboxyheptadecanoyl]-isoGlu)]-[NH2] (Compound 39); Hy-H[Aib]EGSFTSELATILDEQAARDFIAWLIEHKITDkkkkkk([17-carboxyheptadecanoyl]-isoGlu)]-[NH2] (Compound 40); Hy-H[Aib]EGTFTSELATILD[K([19-carboxy-nonadecanoyl]-isoGlu)]QAARDFIAWLIQHKITD-OH (Compound 41); Hy-H[Aib]EGSFTSE[K([19-carboxy-nonadecanoyl]iso-Glu-Peg3-Peg3)]ATILDEQAARDFIAWLIEHKITD-OH (Compound 42); Hy-H[Aib]EGSFTSELATILD[K([19-carboxy-nonadecanoyl]iso-Glu-Peg3-Peg3)]KAARDFIAWLIEHKITD-OH (Compound 43); Hy-H[Aib]EGSFTSELATILEG[K([19-carboxy-nonadecanoyl]iso-Glu-Peg3-Peg3)]AARDFIAWLIEHKITD-OH (Compound 44); Hy-H[Aib]EGSFTSELATILDEQAA[K([19-carboxy-nonadecanoyl]iso-Glu-Peg3-Peg3)]DFIAWLIEHKITD-OH (Compound 45); Hy-H[Aib]EGTFTSELATILDEQAA[K([19-carboxy-nonadecanoyl]iso-Glu-Peg3-Peg3)]DFIAWLIEHKITD-OH (Compound 46). Hy-H[Aib]EGTFSSELATILD[K([17-carboxy-heptadecanoyl]-isoGlu-KEK-Peg3)]QAARDFIAWLIQHKITD-OH (Compound 47); Hy-H[Aib]EGTFSSELATILD[K([19-carboxy-nonadecanoyl]-isoGlu-KEK-Peg3)]QAARDFIAWLIQHKITD-OH (Compound 48); Hy-H[Aib]EGTFSSELATILD[K([17-carboxy-heptadecanoyl]-isoGlu-KEK-Peg3)]QAARDFIAWLIEHKITD-OH (Compound 49); Hy-H[Aib]EGTFSSELATILD[K([19-carboxy-nonadecanoyl]-isoGlu-KEK-Peg3)]QAARDFIAWLIEHKITD-OH (Compound 50); Hy-H[Aib]EGTFTSELATILD[K([19-carboxy-nonadecanoyl]-isoGlu-KEK)]QAARDFIAWLIQHKITD-OH (Compound 51); Hy-H[Aib]EGTFTSELATILD[K([19-carboxy-nonadecanoyl]-isoGlu-KEK-Peg3)]QAARDFIAWLIQHKITD-OH (Compound 52); Hy-H[Aib]EGSFTSE[K([19-carboxy-nonadecanoyl]-isoGlu-KEK-Peg3)]ATILDEQAARDFIAWLIEHKITD-OH (Compound 53); Hy-H[Aib]EGTFTSE[K([19-carboxy-nonadecanoyl]-isoGlu-KEK-Peg3)]ATILDEQAARDFIAWLIEHKITD-OH (Compound 54); Hy-H[Aib]EGSFTSE[K([19-carboxy-nonadecanoyl]iso-Glu-KEK-Peg3-Peg3)]ATILDEQAARDFIAWLIEHKITD-OH (Compound 55); Hy-H[Aib]EGTFTSELATILD[K([19-carboxy-nonadecanoyl]-isoGlu-KEK-Peg3)]QAARDFIAWLIEHKITD-OH (Compound 56); Hy-H[Aib]EGSFTSELATILD[K([19-carboxy-nonadecanoyl]-isoGlu-KEK-Peg3)]QAARDFIAWLIEHKITD-OH (Compound 57); Hy-H[Aib]EGSFTSELATILD[K([19-carboxy-nonadecanoyl]-isoGlu-KEK-Peg3)]QAARDFIAWLIAHKITD-OH (Compound 58); Hy-H[Aib]EGSFTSELATILD[K([19-carboxy-nonadecanoyl]-isoGlu-KEK-Peg3)]KAARDFIAWLIEHKITD-OH (Compound 59); Hy-H[Aib]EGSFTSELATILD[K([19-carboxy-nonadecanoyl]iso-Glu-KEK-Peg3-Peg3)]QAARDFIAWLIEHKITD-OH (Compound 60); Hy-H[Aib]EGSFTSELATILEG[K([19-carboxy-nonadecanoyl]-isoGlu-KEK-Peg3)]AARDFIAWLIEHKITD-OH (Compound 61); Hy-H[Aib]EGSFTSELATILDA[K([19-carboxy-nonadecanoyl]-isoGlu-KEK-Peg3)]AARDFIAWLIEHKITD-OH (Compound 62); Hy-H[Aib]EGSFTSELATILDA[K([19-carboxy-nonadecanoyl]iso-Glu-KEK-Peg3-Peg3)]AARDFIAWLIEHKITD-OH (Compound 63); Hy-H[Aib]EGSFTSELATILDEQAA[K([19-carboxy-nonadecanoyl]-isoGlu-KEK-Peg3)]DFIAWLIEHKITD-OH (Compound 64); Hy-H[Aib]EGTFTSELATILDEQAA[K([19-carboxy-nonadecanoyl]-isoGlu-KEK-Peg3)]DFIAWLIEHKITD-OH (Compound 65); Hy-H[Aib]EGSFTSELATILDEQAA[K([19-carboxy-nonadecanoyl]iso-Glu-KEK-Peg3-Peg3)]DFIAWLIEHKITD-OH (Compound 66); Hy-H[Aib]EGTFTSELATILDEQAA[K([19-carboxy-nonadecanoyl]iso-Glu-KEK-Peg3-Peg3)]DFIAWLIEHKITD-OH (compound 67); or Hy-H[Aib]EGSFTSELATILDAKAA[K([19-carboxy-nonadecanoyl]-isoGlu-KEK-Peg3)]DFIAWLIEHKITD-OH (Compound 68).

[0060] In one embodiment, the dual agonist is H[Aib]EGSFTSELATILD[Ψ]QAARDFIAWLIQHKITD (Sequence ID 34). In one embodiment, the dual agonist is as follows: a. Hy-H[Aib]EGSFTSELATILD[K([17-carboxy-heptadecanoyl]-isoGlu)]QAARDFIAWLIQHKITD-OH(CPD1OH), or b.Hy-H[Aib]EGSFTSELATILD[K([17-carboxy-heptadecanoyl]-isoGlu)]QAARDFIAWLIQHKITD-NH2(CPD1NH2).

[0061] In a preferred embodiment, the double agonist is Hy-H[Aib]EGSFTSELATILD[K([17-carboxy-heptadecanoyl]-isoGlu)]QAARDFIAWLIQHKITD-OH (compound 18).

[0062] In a preferred embodiment, the double agonist is Hy-H[Aib]EGTFTSELATILD[K([17-carboxy-heptadecanoyl]-isoGlu)]QAARDFIAWLIQHKITD-OH (compound 19).

[0063] The dual agonist may be in the form of a pharmaceutically acceptable salt or solvate, such as a pharmaceutically acceptable acid addition salt.

[0064] The present invention also provides compositions comprising the dual agonist of the present invention, or a pharmaceutically acceptable salt or solvate thereof, together with a carrier, excipient, or vehicle, for use in methods of reducing or preventing weight gain, reducing food intake, reducing appetite, promoting weight loss, or treating obesity, morbid obesity, obesity-related gallbladder disease, or obesity-induced sleep apnea, the method comprising the step of administering the dual agonist to a patient in a dose of about 0.1 mg to about 10.0 mg. The carrier may be a pharmaceutically acceptable carrier.

[0065] The composition may be a pharmaceutical composition. The pharmaceutical composition may be formulated as a liquid suitable for administration by injection or infusion. It may be formulated to achieve sustained release of a dual agonist.

[0066] The present invention also provides a dual agonist according to the present invention for use in methods for reducing or preventing weight gain, reducing gastric emptying or intestinal transit, reducing food intake, reducing appetite, or promoting weight loss, the method comprising the step of administering the dual agonist to a patient in a dose of about 0.1 mg to about 10.0 mg.

[0067] The present invention also provides a dual agonist according to the present invention for use in a method for preventing or treating obesity, morbid obesity, obesity-related gallbladder disease, or obesity-induced sleep apnea, the method comprising the step of administering the dual agonist to a patient in a dose of about 0.1 mg to about 10.0 mg.

[0068] The present invention also provides a method for reducing or preventing weight gain, reducing gastric emptying or intestinal transit, reducing food intake, reducing appetite, or promoting weight loss in subjects who require it, the method comprising the step of administering a dual agonist according to the present invention to a subject in a dose of about 0.1 mg to about 10.0 mg.

[0069] The present invention also provides a method for preventing or treating obesity, morbid obesity, obesity-related gallbladder disease, or obesity-induced sleep apnea, the method comprising the step of administering a dual agonist according to the present invention to a subject in a dose of about 0.1 mg to about 10.0 mg.

[0070] The present invention also provides the use of a dual agonist according to the present invention in the preparation of a pharmacopoeia for reducing or preventing weight gain, reducing gastric emptying or intestinal transit, reducing food intake, reducing appetite, or promoting weight loss, wherein the pharmacopoeia is administered to the patient in doses of about 0.1 mg to about 10.0 mg.

[0071] The present invention also provides the use of a dual agonist according to the present invention in the preparation of a pharmaceutical for the prevention or treatment of obesity, morbid obesity, obesity-related gallbladder disease, or obesity-induced sleep apnea, the pharmaceutical being administered to the patient in doses of about 0.1 mg to about 10.0 mg.

[0072] A further aspect provides a therapeutic kit for use in a method of reducing or preventing weight gain, reducing food intake, reducing appetite, promoting weight loss, or treating obesity, morbid obesity, obesity-related gallbladder disease, or obesity-induced sleep apnea, or for reducing or preventing weight gain, reducing gastric emptying or intestinal transit, reducing food intake, reducing appetite, or promoting weight loss, the kit comprising a dual agonist according to the invention, or a pharmaceutically acceptable salt or solvate thereof, the method comprising administering the dual agonist to a patient at a dose of from about 0.1 mg to about 10.0 mg.

[0073] In one aspect, a patient or subject (terms used interchangeably herein) may experience enhanced satiety following administration of the dual agonist. BRIEF DESCRIPTION OF THE DRAWINGS

[0074] [Figure 1] FIG. showing the mean pharmacokinetic profile of Compound 18 after single administration to healthy subjects. [Figure 2] FIG. showing a multiple-ascending dose study design. The upper line shows the number of patients treated with Compound 18, the lower line shows placebo administration, and the diamonds represent safety assessments. [Figure 3] FIG. showing weight changes after repeated ascending dosing in a Phase 1b study. [Figure 4] FIG. showing a randomized (2:2:1:1), parallel-group, double-blind, placebo-controlled study design in which 54 individuals with obesity were administered either 1) Compound 18 2 / 4 / 6 mg, 2) Compound 18 2 / 4 mg, 3) placebo 2 / 4 / 6 mg, or 4) placebo 2 / 4 mg for a period of 12 weeks. DETAILED DESCRIPTION OF THE INVENTION

[0075] Unless otherwise defined herein, scientific and technical terms used in this application have meanings that are generally understood by those skilled in the art. In general, the nomenclature and techniques used herein in relation to chemistry, molecular biology, cell and cancer biology, immunology, microbiology, pharmacology, and protein and nucleic acid chemistry are well known and commonly used in the art.

[0076] All patents, published patent applications, and non-patent literature referenced in this application are incorporated herein by reference. In case of any conflict, this specification, including its specific definitions, shall prevail.

[0077] Each embodiment of the present invention described herein may be taken alone or in combination with one or more other embodiments of the present invention.

[0078] a.Definition Unless otherwise specified, the following definitions are provided for the specific terms used herein.

[0079] Throughout this specification, it will be understood that the word "comprise," and its grammatical variations such as "comprises" or "comprising," imply the inclusion of the described integer or component, or group of integers or components, but not the exclusion of any other integer or component, or group of integers or components.

[0080] The singular forms "a," "an," and "the" include the plural form unless clearly indicated otherwise by the context.

[0081] The term "including" is used to mean "including but not limited to." "Including" and "including but not limited to" can be used interchangeably.

[0082] The terms “patient,” “subject,” and “individual” may be used interchangeably and refer to either a human or a non-human animal. These terms include mammals such as humans, primates, domestic animals (e.g., cattle and pigs), companion animals (e.g., canids and felines), and rodents (e.g., mice and rats).

[0083] In the context of this invention, the term "solvate" means a defined stoichiometric complex formed between a solute (in this case, the peptide or a pharmaceutically acceptable salt thereof according to the present invention) and a solvent. The solvent in question may be, for example, water, ethanol, or another pharmaceutically acceptable, typically small-molecule organic species, such as, but not limited to, acetic acid or lactic acid. When the solvent is water, such a solvate is usually called a hydrate.

[0084] In the context of this invention, the term "agonist" refers to a substance (ligand) that activates the receptor species in question.

[0085] Throughout this specification and the claims, the conventional three-letter and one-letter codes for naturally occurring amino acids, namely A (Ala), G (Gly), L (Leu), I (Ile), V (Val), F (Phe), W (Trp), S (Ser), T (Thr), Y (Tyr), N (Asn), Q (Gln), D (Asp), E (Glu), K (Lys), R (Arg), H (His), M (Met), C (Cys), and P (Pro), as well as the three-letter codes for other commonly recognized α-amino acids, such as sarcosine (Sar), norleucine (Nle), α-aminoisobutyric acid (Aib), 2,3-diaminopropanoic acid (Dap), 2,4-diaminobutanoic acid (Dab), and 2,5-diaminopentanoic acid (ornithine, Orn). Other such α-amino acids, when used in general formulas or sequences herein, may be indicated in square brackets "[]" (e.g., "[Aib]"), especially when the remaining formula or sequence is indicated using single-letter codes. Unless otherwise specified, the amino acid residues in the peptides of the present invention are in the L-configuration. However, D-configuration amino acids may be incorporated. In this context, lowercase amino acid codes represent the D-configuration of that amino acid; for example, "k" represents the D-configuration of lysine (K).

[0086] Among the sequences disclosed herein, there are sequences that incorporate a "Hy-" moiety at the amino terminus (N terminus) and either an "-OH" moiety or an "-NH2" moiety at the carboxyl terminus (C terminus). In such cases, unless otherwise specified, the "Hy-" moiety at the N terminus of the sequence represents a hydrogen atom [i.e., R in the general formula]. 1 =Hydrogen=Hy, corresponding to the presence of a free primary or secondary amino group at the N-terminus], the "-OH" or "-NH2" portion at the C-terminus of the sequence is a hydroxyl group, respectively [for example, R in the general formula] 2 =OH, corresponding to the presence of a C-terminal carboxyl (COOH) group] or amino group [for example, R in the general formula] 2=[NH2], corresponding to the presence of a C-terminal amide (CONH2) group. In each of the sequences of the present invention, the C-terminal "-OH" portion may be replaced with the C-terminal "-NH2" portion, and vice versa.

[0087] "Percent (%) amino acid sequence identity" for GLP-2 polypeptide sequences is defined as the percentage of amino acid residues in a candidate sequence that are identical to those in the wild-type (human) GLP-2 sequence, after aligning the sequences to achieve the highest possible percentage sequence identity, introducing gaps where necessary, and without considering any conservative substitutions as part of the sequence identity. Sequence alignment can be performed by those skilled in the art using techniques well known in the art, for example, using publicly available software such as BLAST, BLAST2, or Align software. See, for example, Altschul et al., Methods in Enzymology 266: 460-480 (1996) or Pearson et al., Genomics 46: 24-36, 1997.

[0088] In the context of the present invention, the percentage sequence identity used herein can be determined by using these programs with their initial settings. More generally, those skilled in the art can easily determine appropriate parameters for determining the alignment, including any algorithm necessary to achieve the maximum alignment over the full length of the sequences being compared.

[0089] double agonist compounds In the present invention, a dual agonist has the biological activity of at least one GLP-1 and at least one GLP-2. Exemplary GLP-1 physiological activity includes reducing the rate of intestinal transport, reducing the rate of gastric emptying, reducing appetite, food intake, or body weight, and improving glucose control and glucose tolerance. Exemplary GLP-2 physiological activity includes resulting in increased intestinal mass (e.g., small intestine or colon), intestinal repair, and improved intestinal barrier function (i.e., decreased intestinal permeability). These parameters can be evaluated in in vivo assays that determine the mass and permeability of the intestine or a portion thereof after treating test animals with a dual agonist.

[0090] Dual agonists possess agonist activity at GLP-1 and GLP-2 receptors, such as human GLP-1 and GLP-2 receptors. (EC) 50 The value can be used as a numerical measure of agonist efficacy at a given receptor. 50 The value is a measure of the concentration (e.g., mol / L) of a compound required to achieve half of its maximum activity in a particular assay. 50 Lower numerical EC 50 Compounds possessing this characteristic may be considered to have higher potency at their receptor than the reference compound.

[0091] GLP-1 activity In some embodiments, the dual agonist, when evaluated using the GLP-1 receptor efficacy assay described in the examples below, showed improved EC levels at the GLP-1 receptor (e.g., human GLP-1 receptor). 50 However, the values ​​are less than 2.0 nM, less than 1.5 nM, less than 1.0 nM, less than 0.9 nM, less than 0.8 nM, less than 0.7 nM, less than 0.6 nM, less than 0.5 nM, less than 0.4 nM, less than 0.3 nM, less than 0.2 nM, less than 0.1 nM, less than 0.09 nM, less than 0.08 nM, less than 0.07 nM, less than 0.06 nM, less than 0.05 nM, and less than 0.04 nM.

[0092] In some embodiments, dual agonists, when evaluated using the GLP-1 receptor efficacy assay described in the following examples, show that EC at the GLP-1 receptor is effective. 50 However, these ranges are 0.005~2.5nM, 0.01nM~2.5nM, 0.025~2.5nM, 0.005~2.0nM, 0.01nM~2.0nM, 0.025~2.0nM, 0.005~1.5nM, 0.01nM~1.5nM, 0.025~1.5nM, 0.005~1.0nM, 0.01nM~1.0nM, 0.025~1.0nM, 0.005~0.5nM, 0.01nM~0.5nM, 0.025~0.5nM, 0.005~0.25nM, 0.01nM~0.25nM, and 0.025~0.25nM.

[0093] An alternative measure of GLP-1 agonist activity can be derived by comparing the potency of a dual agonist to that of a known (or reference) GLP-1 agonist when both are measured in the same assay. Therefore, the relative potency at the GLP-1 receptor can be defined as follows: [EC 50 (Reference Agonist)] / [EC 50 (Double agonist).

[0094] Therefore, a value of 1 indicates that the dual agonist and the reference agonist have equal potency, and a value >1 indicates that the dual agonist has higher potency (i.e., lower EC) than the reference agonist. 50 This indicates that the dual agonist has lower potency (i.e., higher EC) than the reference agonist, and a value of <1 indicates that the dual agonist has lower potency (i.e., higher EC) than the reference agonist. 50 This indicates that it has ).

[0095] The reference GLP-1 agonist may be, for example, human GLP-1(7-37), liraglutide (NN2211, Victoza), or exendin-4, but liraglutide is preferred.

[0096] Typically, the relative effects are 0.001 to 100, for example, 0.001 to 10, 0.001 to 5, 0.001 to 1, 0.001 to 0.5, 0.001 to 0.1, 0.001 to 0.05, or 0.001 to 0.01; 0.01 to 10, 0.01 to 5, 0.01 to 1, 0.01 to 0.5, 0.01 to 0.1, or 0.01 to 0.05; 0.05 to 10, 0.05 to 5, 0.05 to 1, 0.05 to 0.5, or 0.05 to 0.1; 0.1 to 10, 0.1 to 5, 0.1 to 1, or 0.1 to 0.5; 0.5 to 10, 0.5 to 5, or 0.5 to 1; 1 to 10, or 1 to 5; or 5 to 10.

[0097] The dual agonists described in the examples below have slightly lower GLP-1 potency than liraglutide, and therefore may have relative potency of, for example, 0.01 to 1, 0.01 to 0.5, or 0.01 to 0.1.

[0098] In contrast, the dual agonists of the present invention exhibit higher potency in the GLP-1 receptor (e.g., human GLP-1 receptor) than wild-type human GLP-2 (hGLP-2(1-33)) or [Gly2]-hGLP-2(1-33) (i.e., human GLP-2 with glycine at position 2, also known as teduglutide). Therefore, the relative potency of the dual agonists in the GLP-1 receptor compared to hGLP-2(1-33) or teduglutide can be greater than 1, typically greater than 5 or greater than 10, up to 100, up to 500, and even greater.

[0099] GLP-2 activity In some embodiments, dual agonists, when evaluated using the GLP-2 receptor efficacy assay described in the examples below, show improved EC levels at the GLP-2 receptor (e.g., human GLP-2 receptor). 50However, the levels are less than 2.0 nM, less than 1.5 nM, less than 1.0 nM, less than 0.9 nM, less than 0.8 nM, less than 0.7 nM, less than 0.6 nM, less than 0.5 nM, less than 0.4 nM, less than 0.3 nM, less than 0.2 nM, less than 0.1 nM, less than 0.09 nM, less than 0.08 nM, less than 0.07 nM, less than 0.06 nM, less than 0.05 nM, less than 0.04 nM, less than 0.03 nM, less than 0.02 nM, or less than 0.01 nM.

[0100] In some embodiments, dual agonists, when evaluated using the GLP-2 receptor efficacy assay described in the examples below, showed EC at the GLP-2 receptor. 50 However, these ranges are 0.005~2.0nM, 0.01nM~2.0nM, 0.025~2.0nM, 0.005~1.5nM, 0.01nM~1.5nM, 0.025~1.5nM, 0.005~1.0nM, 0.01nM~1.0nM, 0.025~1.0nM, 0.005~0.5nM, 0.01nM~0.5nM, 0.025~0.5nM, 0.005~0.25nM, 0.01nM~0.25nM, and 0.025~0.25nM.

[0101] An alternative measure of GLP-2 agonist activity can be derived by comparing the potency of a dual agonist to the potency of a known (or reference) GLP-2 agonist when both are measured in the same assay. Therefore, relative potency at the GLP-2 receptor can be defined as follows: [EC 50 (Reference Agonist)] / [EC 50 (Double agonist).

[0102] Therefore, a value of 1 indicates that the dual agonist and the reference agonist have equal potency, and a value >1 indicates that the dual agonist has higher potency (i.e., lower EC) than the reference agonist. 50 This indicates that the dual agonist has lower potency (i.e., higher EC) than the reference agonist, and a value of <1 indicates that the dual agonist has lower potency (i.e., higher EC) than the reference agonist. 50 This indicates that it has ).

[0103] The reference GLP-2 agonist may be, for example, human GLP-2(1-33) or teduglutide ([Gly2]-hGLP-2(1-33)), but teduglutide is preferred. Typically, the relative effects are 0.001 to 100, for example, 0.001 to 10, 0.001 to 5, 0.001 to 1, 0.001 to 0.5, 0.001 to 0.1, 0.001 to 0.05, or 0.001 to 0.01; 0.01 to 10, 0.01 to 5, 0.01 to 1, 0.01 to 0.5, 0.01 to 0.1, or 0.01 to 0.05; 0.05 to 10, 0.05 to 5, 0.05 to 1, 0.05 to 0.5, or 0.05 to 0.1; 0.1 to 10, 0.1 to 5, 0.1 to 1, or 0.1 to 0.5; 0.5 to 10, 0.5 to 5, or 0.5 to 1; 1 to 10, or 1 to 5; or 5 to 10.

[0104] The dual agonists described in the following examples have slightly lower GLP-2 potency than teduglutide, and therefore may have relative potency of, for example, 0.01 to 1, 0.01 to 0.5, or 0.01 to 0.1.

[0105] In contrast, the dual agonists of the present invention exhibit higher potency at the GLP-2 receptor (e.g., human GLP-2 receptor) than human GLP-1(7-37), liraglutide (NN2211, Victoza), or exendin-4. Therefore, the relative potency of the dual agonists at the GLP-2 receptor compared to human GLP-1(7-37), liraglutide (NN2211, Victoza), or exendin-4 may be greater than 1, typically greater than 5, or greater than 10, up to 100, up to 500, and even greater (provided the reference GLP-1 agonist exhibits detectable activity at the GLP-2 receptor).

[0106] It should be understood that the balance between GLP-1 agonist activity and GLP-2 agonist activity is far more important than the absolute potency of a dual agonist at each receptor. Therefore, as long as a dual agonist compound exerts an acceptable relative level of potency at both receptors, it is perfectly acceptable for its absolute GLP-1 or GLP-2 potency to be lower than that of known agonists at those receptors. Any apparent lack of absolute potency can be compensated for by increasing the dose as needed.

[0107] b. Substituents The double agonist of the present invention has a side chain with substituent Z 1 - or Z 1 -Z 2 - Conjugates with a residue Ψ which contains a residue of Lys, Arg, Orn, Dap, or Dab, in the formula Z 1 is CH3-(CH2) 10-22 -(CO)- or HOOC-(CH2) 10-22 -(CO)- represents the part, Z 2 If present, it represents a spacer.

[0108] Spacer Z 2 is, -Z S1 -, -Z S1 -Z S2 -, -Z S2 -Z S1 , -Z S2 -, -Z S3 -, -Z S1 Z S3 -, -Z S2 Z S3 -, -Z S3 Z S1 -, -Z S3 Z S2 -, -Z S1 Z S2 Z S3 -, -Z S1 Z S3 Z S2 -, -Z S2 Z S1 Z S3 -, -Z S2 Z S3 Z S1-, -Z S3 Z S1 Z S2 -, -Z S3 Z S2 Z S1 -, Z S2 Z S3 Z S2 - Selected from, in the formula, Z S1 isoGlu, β-Ala, isoLys, or 4-aminobutanoyl, Z S2 is -(Peg3) m -where m is 1, 2, or 3, Z S3 - is a peptide sequence consisting of 1 to 6 amino acid units selected from the group consisting of A, L, S, T, Y, Q, D, E, K, k, R, H, F, and G.

[0109] In some embodiments, Z 2 is, equation -Z S1 -, -Z S1 -Z S2 -, -Z S2 -Z S1 , or Z S2 It is a spacer, in the formula -Z S1 - is isoGlu, β-Ala, isoLys, or 4-aminobutanoyl, and -Z S2 - is -(Peg3) m -where m is 1, 2, or 3.

[0110] I don't want to be bound by theory, Z 1 The hydrocarbon chains bind to albumin in the bloodstream, which is thought to protect the dual agonist of the present invention from enzymatic degradation, potentially extending the half-life of the dual agonist.

[0111] Substituents can also modulate the efficacy of the dual agonist with respect to the GLP-2 receptor and / or GLP-1 receptor.

[0112] substituent Z 1 - or Z 1 -Z 2The substituent conjugates from the alpha carbon of the relevant amino acid residue to the functional group at the distal end of the side chain. Therefore, the normal ability of the amino acid (Lys, Arg, Orn, Dab, Dap) side chain to participate in interactions mediated by its functional group (e.g., intramolecular and intermolecular interactions) can be reduced or completely eliminated by the presence of the substituent. Thus, the overall properties of a double agonist may be relatively insensitive to changes in the actual amino acid conjugated with the substituent. As a result, it is thought that any of the residues Lys, Arg, Orn, Dab, or Dap can be located at any position where Ψ is permitted. However, in certain embodiments, it may be advantageous that the amino acid conjugated by the substituent is Lys or Orn.

[0113] Z 1 The portion can be covalently bonded to a functional group in the amino acid side chain, or to a spacer Z. 2 It is conjugated with the amino acid side chain functional group via this mechanism.

[0114] The term “conjugated” is used herein to describe a covalent bond between one identifiable chemical part and another, and the structural relationship between such parts. It should not be construed as implying any particular method of synthesis.

[0115] Z 1 , Z S1 , Z S2 , Z S3 The bond between the amino acid side chains to which the substituents are attached (collectively referred to herein as Ψ) is peptidic. In other words, the units may be bonded by amide condensation reactions.

[0116] Z 1This includes a hydrocarbon chain having 10 to 24 carbon (C) atoms, for example, 10 to 22 C atoms, for example, 10 to 20 C atoms. Preferably, it has at least 10 or at least 11 C atoms, and preferably, it has 20 or 19 or fewer C atoms, for example, 18 or 17 or fewer C atoms. For example, the hydrocarbon chain may contain 12, 13, 14, 15, 16, 17, 18, 19, or 20 carbon atoms. For example, it may contain 18 or 20 carbon atoms.

[0117] In some embodiments, Z 1 The group is selected from dodecanoyl, tetradecanoyl, hexadecanoyl, octadecanoyl, and eicosaenoyl, preferably hexadecanoyl, octadecanoyl, or eicosaenoyl, more preferably octadecanoyl or eicosaenoyl.

[0118] Alternative Z 1 The group has the formula HOOC-(CH2) 12-22 -COOH long-chain saturated α,ω-dicarboxylic acids, preferably long-chain saturated α,ω-dicarboxylic acids having an even number of carbon atoms in the aliphatic chain. For example, Z 1 This could be: 13-Carboxytridecanoyl, i.e., HOOC-(CH2) 12 -(CO)-; 15-Carboxypentadecanoyl, i.e., HOOC-(CH2) 14 -(CO)-; 17-Carboxyheptadecanoyl, i.e., HOOC-(CH2) 16 -(CO)-; 19-Carboxynonadecanoyl, i.e., HOOC-(CH2) 18 -(CO)-; or 21-Carboxyhexenoyl, i.e., HOOC-(CH2) 20 -(CO)-

[0119] As mentioned above, Z 1 Spacer Z 2It may be conjugated with the amino acid side chain by Z. If present, the spacer is Z 1 It is also bound to the amino acid side chain.

[0120] Spacer Z 2 is, -Z S1 -, -Z S1 -Z S2 -, -Z S2 -Z S1 , -Z S2 -, -Z S3 -, -Z S1 Z S3 -, -Z S2 Z S3 -, -Z S3 Z S1 -, -Z S3 Z S2 -, -Z S1 Z S2 Z S3 -, -Z S1 Z S3 Z S2 -, -Z S2 Z S1 Z S3 -, -Z S2 Z S3 Z S1 -, -Z S3 Z S1 Z S2 -, -Z S3 Z S2 Z S1 -, Z S2 Z S3 Z S2 - has, in the formula, -Z S1 - is isoGlu, β-Ala, isoLys, or 4-aminobutanoyl, -Z S2 - is -(Peg3) m -where m is 1, 2, or 3, -Z S3- is a peptide sequence consisting of 1 to 6 amino acid units independently selected from the group consisting of A (Ala), L (Leu), S (Ser), T (Thr), Y (Tyr), Q (Gln), D (Asp), E (Glu), K (L-Lys), k (D-Lys), R (Arg), H (His), F (Phe), and G (Gly).

[0121] The terms "isoGlu" and "isoLys" refer to amino acid residues that participate in the binding via their side-chain carboxyl or amine functional groups. Therefore, isoGlu participates in the binding via its alpha-amino and side-chain carboxyl groups, while isoLys participates via its carboxyl and side-chain amino groups. In the context of this specification, the terms "γ-Glu" and "isoGlu" are used interchangeably.

[0122] The term Peg3 is used to refer to the 8-amino-3,6-dioxaoctanoyl group.

[0123] Z S3 This could be, for example, the length of 3 to 6 amino acids, i.e., the length of 3, 4, 5, or 6 amino acids.

[0124] In some embodiments, Z S3 The amino acids are independently selected from K, k, E, A, T, I, and L, for example from K, k, E, and A, or for example from K, k, and E.

[0125] Typically, Z S3 This comprises at least one charged amino acid (K, k, R, or E, e.g., K, k, or E) and preferably two or three or more charged amino acids. In some embodiments, this comprises at least two positively charged amino acids (K, k, or R, particularly K or k) or at least one positively charged amino acid (K, k, or R, particularly K or k) and at least one uncharged amino acid (E). In some embodiments, Z S3 All amino acid residues are charged. For example, Z S3 This can be a chain of amino acids alternating between positive and negative charges.

[0126] Z S3 Examples of parts include KEK, EKEKEK (sequence number 7), kkkkkk (sequence number 179), EkEkEk (sequence number 8), AKAAEK (sequence number 9), AKEKEK (sequence number 10), and ATILEK (sequence number 11).

[0127] Although not bound by theory, Z S3 It is thought that incorporating this compound into the linker between the fatty acid chain and the peptide backbone can increase the half-life of the dual agonist by enhancing its affinity for serum albumin.

[0128] In some embodiments, -Z 2 - is -Z S1 - or -Z S1 -Z S2 - and in other words, -Z 2 - is selected from the following: isoGlu(Peg3) 0-3 , β-Ala(Peg3) 0-3 , isoLys(Peg3) 0-3 , and 4-aminobutanoyl(PEG3) 0-3 .

[0129] Therefore, substituent Z 1 Specific examples of these include dodecanoyl, tetradecanoyl, hexadecanoyl, octadecanoyl, eicosaenoyl, 13-carboxy-tridecanoyl, 15-carboxy-pentadecanoyl, 17-carboxy-heptadecanoyl, 19-carboxy-nonadecanoyl, and 21-carboxy-heneicosaenoyl.

[0130] More broadly speaking, -Z 2 - is, -Z S1 -, -Z S1 -Z S2 -, -Z S3 -Z S1-, -Z S1 -Z S3 -, -Z S1 -Z S3 -Z S2 -, -Z S3 -Z S2 -Z S1 - or Z S3 - is possible. Therefore, -Z 2 - can be selected from the following group: isoGlu(Peg3) 0-3 ; β-Ala(Peg3) 0-3 ; isoLys(Peg3) 0-3 ; 4-aminobutanoyl(PEG3) 0-3; isoGlu(KEK)(Peg3) 0-3 ; β-Ala(KEK)(Peg3) 0-3 ; isoLys(KEK)(Peg3) 0-3 ; 4-aminobutanoyl(KEK)(PEG3) 0-3 ; KEK(isoGlu) (SEQ ID NO: 180); KEK(β-Ala) (SEQ ID NO: 181); KEK(isoLys) (Sequence ID 182); KEK(4-aminobutanoyl) (SEQ ID NO: 183); isoGlu(KEK) (SEQ ID NO: 6); β-Ala(KEK) (SEQ ID NO: 184); isoLys(KEK) (Sequence ID 185); 4-aminobutanoyl (KEK) (SEQ ID NO: 186); KEK(isoGlu)(Peg3) 0-3 ; KEK(β-Ala)(Prg3) 0-3 ; KEK(isoLys)(Peg3) 0-3 and KEK(4-aminobutanoyl)(PEG3) 0-3 ;

[0131] substituent Z 1 -Z 2 Specific examples of - include the following: [Dodecanoyl]-isoGlu, [Tetradecanoyl]-isoGlu, [Hexadecanoyl]-isoGlu, [Octadecanoyl]-isoGlu, [Eicosaenoyl]-isoGlu, [Hexadecanoyl]-βAla, [Octadecanoyl]-βAla, [Eicosacanoyl]-βAla, [Tetradecanoyl]-βAla, [Dodecanoyl]-βAla, [Dodecanoyl]-isoGlu-Peg3, [Tetradecanoyl]-isoGlu-Peg3, [Hexadecanoyl]-isoGlu-Peg3, [Octadecanoyl]-isoGlu-Peg3, [Eicosaenoyl]-isoGlu-Peg3, [Dodecanoyl]-βAla-Peg3, [Tetradecanoyl]-βAla-Peg3, [Hexadecanoyl]-βAla-Peg3, [Octadecanoyl]-βAla-Peg3, [Eicosaenoyl]-βAla-Peg3, [Dodecanoyl]-isoGlu-Peg3-Peg3, [Tetradecanoyl]-isoGlu-Peg3-Peg3, [Hexadecanoyl]-isoGlu-Peg3-Peg3, [Octadecanoyl]-isoGlu-Peg3-Peg3, [Eicosaenoyl]-isoGlu-Peg3-Peg3, [Dodecanoyl]-βAla-Peg3-Peg3, [Tetradecanoyl]-βAla-Peg3-Peg3, [Hexadecanoyl]-βAla-Peg3-Peg3, [Octadecanoyl]-βAla-Peg3-Peg3, [Eicosaenoyl]-βAla-Peg3-Peg3, [Dodecanoyl]-isoGlu-Peg3-Peg3-Peg3, [Tetradecanoyl]-isoGlu-Peg3-Peg3-Peg3, [Hexadecanoyl]-isoGlu-Peg3-Peg3-Peg3, [Octadecanoyl]-isoGlu-Peg3-Peg3-Peg3, [Eicosaenoyl]-isoGlu-Peg3-Peg3-Peg3, [Dodecanoyl]-βAla-Peg3-Peg3-Peg3, [Tetradecanoyl]-βAla-Peg3-Peg3-Peg3, [Hexadecanoyl]-βAla-Peg3-Peg3-Peg3, [Octadecanoyl]-βAla-Peg3-Peg3-Peg3, [Eicosaenoyl]-βAla-Peg3-Peg3-Peg3, [Dodecanoyl]-isoLys, [Tetradecanoyl]-isoLys, [Hexadecanoyl]-isoLys, [Octadecanoyl]-isoLys, [Eicosaenoyl]-isoLys, [Hexadecanoyl]-[4-aminobutanoyl], [Octadecanoyl]-[4-aminobutanoyl], [Eicosanoyl]-[4-aminobutanoyl], [Tetradecanoyl]-[4-aminobutanoyl], [Dodecanoyl]-[4-aminobutanoyl], [Dodecanoyl]-isoLys-Peg3, [Tetradecanoyl]-isoLys-Peg3, [Hexadecanoyl]-isoLys-Peg3, [Octadecanoyl]-isoLys-Peg3, [Eicosaenoyl]-isoLys-Peg3, [Dodecanoyl]-[4-aminobutanoyl]-PEG3, [Tetradecanoyl]-[4-aminobutanoyl]-PEG3, [Hexadecanoyl]-[4-aminobutanoyl]-PEG3, [Octadecanoyl]-[4-aminobutanoyl]-PEG3, [Eicosaenoyl]-[4-aminobutanoyl]-PEG3, [Dodecanoyl]-isoLys-Peg3-Peg3, [Tetradecanoyl]-isoLys-Peg3-Peg3, [Hexadecanoyl]-isoLys-Peg3-Peg3, [Octadecanoyl]-isoLys-Peg3-Peg3, [Eicosaenoyl]-isoLys-Peg3-Peg3, [Dodecanoyl]-[4-aminobutanoyl]-Peg3-Peg3, [Tetradecanoyl]-[4-aminobutanoyl]-Peg3-Peg3, [Hexadecanoyl]-[4-aminobutanoyl]-Peg3-Peg3, [Octadecanoyl]-[4-aminobutanoyl]-Peg3-Peg3, [Eicosaenoyl]-[4-aminobutanoyl]-Peg3-Peg3, [Dodecanoyl]-isoLys-Peg3-Peg3-Peg3, [Tetradecanoyl]-isoLys-Peg3-Peg3-Peg3, [Hexadecanoyl]-isoLys-Peg3-Peg3-Peg3, [Octadecanoyl]-isoLys-Peg3-Peg3-Peg3, [Eicosaenoyl]-isoLys-Peg3-Peg3-Peg3, [Dodecanoyl]-[4-aminobutanoyl]-Peg3-Peg3-Peg3, [Tetradecanoyl]-[4-aminobutanoyl]-Peg3-Peg3-Peg3, [Hexadecanoyl]-[4-aminobutanoyl]-Peg3-Peg3-Peg3, [Octadecanoyl]-[4-aminobutanoyl]-Peg3-Peg3-Peg3, [Eicosaenoyl]-[4-aminobutanoyl]-Peg3-Peg3-Peg3, [13-Carboxy-tridecanoyl]-isoGlu, [15-Carboxy-pentadecanoyl]-isoGlu, [17-Carboxy-heptadecanoyl]-isoGlu, [19-Carboxy-nonadecanoyl]-isoGlu, [21-Carboxy-heneicosanoyl]-isoGlu, [17-Carboxy-heptadecanoyl]-βAla, [19-Carboxy-nonadecanoyl]-βAla, [21-Carboxy-heneicosanoyl]-βAla, [15-Carboxy-pentadecanoyl]-βAla, [13-Carboxy-tridecanoyl]-βAla, [13-Carboxy-tridecanoyl]-isoGlu-Peg3, [15-Carboxy-pentadecanoyl]-isoGlu-Peg3, [17-Carboxy-heptadecanoyl]-isoGlu-Peg3, [19-Carboxy-nonadecanoyl]-isoGlu-Peg3, [21-Carboxy-heneicosanoyl]-isoGlu-Peg3, [13-Carboxy-tridecanoyl]-βAla-Peg3, [15-Carboxy-pentadecanoyl]-βAla-Peg3, [17-Carboxy-heptadecanoyl]-βAla-Peg3, [19-Carboxy-nonadecanoyl]-βAla-Peg3, [21-Carboxy-heneicosanoyl]-βAla-Peg3, [13-carboxy-tridecanoyl]-isoGlu-Peg3-Peg3, [15-carboxy-pentadecanoyl]-isoGlu-Peg3-Peg3, [17-carboxy-heptadecanoyl]-isoGlu-Peg3-Peg3, [19-carboxy-nonadecanoyl]-isoGlu-Peg3-Peg3, [21-carboxy-heneicosanoyl]-isoGlu-Peg3-Peg3, [13-Carboxy-tridecanoyl]-βAla-Peg3-Peg3, [15-Carboxy-pentadecanoyl]-βAla-Peg3-Peg3, [17-Carboxy-heptadecanoyl]-βAla-Peg3-Peg3, [19-Carboxy-nonadecanoyl]-βAla-Peg3-Peg3, [21-Carboxy-heneicosanoyl]-βAla-Peg3-Peg3, [13-carboxy-tridecanoyl]-isoGlu-Peg3-Peg3-Peg3, [15-carboxy-pentadecanoyl]-isoGlu-Peg3-Peg3-Peg3, [17-carboxy-heptadecanoyl]-isoGlu-Peg3-Peg3-Peg3, [19-carboxy-nonadecanoyl]-isoGlu-Peg3-Peg3-Peg3, [21-carboxy-heneicosanoyl]-isoGlu-Peg3-Peg3-Peg3, [13-Carboxy-tridecanoyl]-βAla-Peg3-Peg3-Peg3, [15-Carboxy-pentadecanoyl]-βAla-Peg3-Peg3-Peg3, [17-Carboxy-heptadecanoyl]-βAla-Peg3-Peg3-Peg3, [19-Carboxy-nonadecanoyl]-βAla-Peg3-Peg3-Peg3, [21-Carboxy-heneicosanoyl]-βAla-Peg3-Peg3-Peg3, [13-Carboxy-tridecanoyl]-isoLys, [15-Carboxy-pentadecanoyl]-isoLys, [17-Carboxy-heptadecanoyl]-isoLys, [19-Carboxy-nonadecanoyl]-isoLys, [21-Carboxy-heneicosanoyl]-isoLys, [17-Carboxy-heptadecanoyl]-[4-aminobutanoyl], [19-Carboxy-nonadecanoyl]-[4-aminobutanoyl], [21-Carboxy-heneicosayl]-[4-aminobutanoyl], [15-Carboxy-pentadecanoyl]-[4-aminobutanoyl], [13-Carboxy-tridecanoyl]-[4-aminobutanoyl], [13-Carboxy-tridecanoyl]-isoLys-Peg3, [15-Carboxy-pentadecanoyl]-isoLys-Peg3, [17-Carboxy-heptadecanoyl]-isoLys-Peg3, [19-Carboxy-nonadecanoyl]-isoLys-Peg3, [21-Carboxy-heneicosanoyl]-isoLys-Peg3, [13-Carboxy-tridecanoyl]-[4-aminobutanoyl]-PEG3, [15-Carboxy-pentadecanoyl]-[4-aminobutanoyl]-PEG3, [17-Carboxy-heptadecanoyl]-[4-aminobutanoyl]-PEG3, [19-Carboxy-nonadecanoyl]-βAla-Peg3, [21-Carboxy-heneicosanoyl]-βAla-Peg3, [13-Carboxy-tridecanoyl]-isoLys-Peg3-Peg3, [15-Carboxy-pentadecanoyl]-isoLys-Peg3-Peg3, [17-Carboxy-heptadecanoyl]-isoLys-Peg3-Peg3, [19-Carboxy-nonadecanoyl]-isoLys-Peg3-Peg3, [21-Carboxy-heneicosanoyl]-isoLys-Peg3-Peg3, [13-Carboxy-tridecanoyl]-[4-aminobutanoyl]-Peg3-Peg3, [15-Carboxy-pentadecanoyl]-[4-aminobutanoyl]-Peg3-Peg3, [17-Carboxy-heptadecanoyl]-[4-aminobutanoyl]-Peg3-Peg3, [19-Carboxy-nonadecanoyl]-[4-aminobutanoyl]-Peg3-Peg3, [21-Carboxy-heneicosayl]-[4-aminobutanoyl]-Peg3-Peg3, [13-carboxy-tridecanoyl]-isoLys-Peg3-Peg3-Peg3, [15-carboxy-pentadecanoyl]-isoLys-Peg3-Peg3-Peg3, [17-carboxy-heptadecanoyl]-isoLys-Peg3-Peg3-Peg3, [19-carboxy-nonadecanoyl]-isoLys-Peg3-Peg3-Peg3, [21-carboxy-heneicosanoyl]-isoLys-Peg3-Peg3-Peg3, [13-Carboxy-tridecanoyl]-[4-aminobutanoyl]-Peg3-Peg3-Peg3, [15-Carboxy-pentadecanoyl]-[4-aminobutanoyl]-Peg3-Peg3-Peg3, [17-Carboxy-heptadecanoyl]-[4-aminobutanoyl]-Peg3-Peg3-Peg3, [19-Carboxy-nonadecanoyl]-[4-aminobutanoyl]-Peg3-Peg3-Peg3 and [21-Carboxy-heneicosaenoyl]-[4-aminobutanoyl]-Peg3-Peg3-Peg3.

[0132] substituent Z 1 -Z 2 Further examples of this include: [Dodecanoyl]-isoLys, [Tetradecanoyl]-isoLys, [Hexadecanoyl]-isoLys, [Octadecanoyl]-isoLys, [Eicosaenoyl]-isoLys, [Hexadecanoyl]-[4-aminobutanoyl], [Octadecanoyl]-[4-aminobutanoyl], [Eicosanoyl]-[4-aminobutanoyl], [Tetradecanoyl]-[4-aminobutanoyl], [Dodecanoyl]-[4-aminobutanoyl], [Hexadecanoyl]-KEK, [Octadecanoyl]-KEK, [Eicosacanoyl]-KEK, [Tetradecanoyl]-KEK, [Dodecanoyl]-KEK, [Dodecanoyl]-PEG3, [Tetradecanoyl]-PEG3, [Hexadecanoyl]-PEG3, [Octadecanoyl]-Peg3, [Eicosaenoyl]-Peg3, [Dodecanoyl]-Peg3-Peg3, [Tetradecanoyl]-Peg3-Peg3, [Hexadecanoyl]-Peg3-Peg3, [Octadecanoyl]-Peg3-Peg3, [Eicosaenoyl]-Peg3-Peg3, [Dodecanoyl]-Peg3-Peg3-Peg3, [Tetradecanoyl]-Peg3- Peg3-Peg3, [Hexadecanoyl]-Peg3-Peg3-Peg3, [Octadecanoyl]- Peg3-Peg3-Peg3, [eikosanoyl]-Peg3-Peg3-Peg3, Dodecanoyl-isoLys-Peg3, Tetradecanoyl-isoLys-Peg3, Hexadecanoyl-isoLys-Peg3, Octadecanoyl-isoLys-Peg3, Eicosaenoyl-isoLys-Peg3, [Dodecanoyl]-[4-aminobutanoyl]-PEG3, [Tetradecanoyl]-[4-aminobutanoyl]-PEG3, [Hexadecanoyl]-[4-aminobutanoyl]-PEG3, [Octadecanoyl]-[4-aminobutanoyl]-PEG3, [Eicosaenoyl]-[4-aminobutanoyl]-PEG3, [Dodecanoyl]-KEK-Peg3, [Tetradecanoyl]-KEK-Peg3, [Hexadecanoyl]-KEK-Peg3, [Octadecanoyl]-KEK-Peg3, [Eicosaenoyl]-KEK-Peg3, [Dodecanoyl]-isoLys-Peg3-Peg3, [Tetradecanoyl]-isoLys-Peg3-Peg3, [Hexadecanoyl]-isoLys-Peg3-Peg3, [Octadecanoyl]-isoLys-Peg3-Peg3, [Eicosaenoyl]-isoLys-Peg3-Peg3, [Dodecanoyl]-[4-aminobutanoyl]-Peg3-Peg3, [Tetradecanoyl]-[4-aminobutanoyl]-Peg3-Peg3, [Hexadecanoyl]-[4-aminobutanoyl]-Peg3-Peg3, [Octadecanoyl]-[4-aminobutanoyl]-Peg3-Peg3, [Eicosaenoyl]-[4-aminobutanoyl]-Peg3-Peg3, [Dodecanoyl]-KEK-Peg3-Peg3, [Tetradecanoyl]-KEK-Peg3-Peg3, [Hexadecanoyl]-KEK-Peg3-Peg3, [Octadecanoyl]-KEK-Peg3-Peg3, [Eicosaenoyl]-KEK-Peg3-Peg3, [Dodecanoyl]-isoLys-Peg3-Peg3-Peg3, [Tetradecanoyl]-isoLys-Peg3-Peg3-Peg3, [Hexadecanoyl]-isoLys-Peg3-Peg3-Peg3, [Octadecanoyl]-isoLys-Peg3-Peg3-Peg3, [Eicosaenoyl]-isoLys-Peg3-Peg3-Peg3, [Dodecanoyl]-[4-aminobutanoyl]-Peg3-Peg3-Peg3, [Tetradecanoyl]-[4-aminobutanoyl]-Peg3-Peg3-Peg3, [Hexadecanoyl]-[4-aminobutanoyl]-Peg3-Peg3-Peg3, [Octadecanoyl]-[4-aminobutanoyl]-Peg3-Peg3-Peg3, [Eicosaenoyl]-[4-aminobutanoyl]-Peg3-Peg3-Peg3, [Dodecanoyl]-KEK-Peg3-Peg3-Peg3, [Tetradecanoyl]-KEK-Peg3-Peg3-Peg3, [Hexadecanoyl]-KEK-Peg3-Peg3-Peg3, [Octadecanoyl]-KEK-Peg3-Peg3-Peg3, [Eicosaenoyl]-KEK-Peg3-Peg3-Peg3, [Dodecanoyl]-isoGlu-KEK-Peg3, [Tetradecanoyl]-isoGlu-KEK-Peg3, [Hexadecanoyl]-isoGlu-KEK-Peg3, [Octadecanoyl]-isoGlu-KEK-Peg3, [Eicosaenoyl]-isoGlu-KEK-Peg3, [Dodecanoyl]-[4-aminobutanoyl]-KEK-Peg3, [Tetradecanoyl]-[4-aminobutanoyl]-KEK-Peg3, [Hexadecanoyl]-[4-aminobutanoyl]-KEK-Peg3, [Octadecanoyl]-[4-aminobutanoyl]-KEK-Peg3, [Eicosaenoyl]-[4-aminobutanoyl]-KEK-Peg3, [Dodecanoyl]-isoLys-KEK-Peg3, [Tetradecanoyl]-isoLys-KEK-Peg3, [Hexadecanoyl]-isoLys-KEK-Peg3, [Octadecanoyl]-isoLys-KEK-Peg3, [Eicosaenoyl]-isoLys-KEK-Peg3, [Dodecanoyl]-βAla-KEK-Peg3, [Tetradecanoyl]-βAla-KEK-Peg3, [Hexadecanoyl]-βAla-KEK-Peg3, [Octadecanoyl]-βAla-KEK-Peg3, [Eicosaenoyl]-βAla-KEK-Peg3, [Dodecanoyl]-isoGlu-KEK-Peg3-Peg3, [Tetradecanoyl]-isoGlu-KEK-Peg3-Peg3, [Hexadecanoyl]-isoGlu-KEK-Peg3-Peg3, [Octadecanoyl]-isoGlu-KEK-Peg3-Peg3, [Eicosaenoyl]-isoGlu-KEK-Peg3-Peg3, [Dodecanoyl]-βAla-KEK-Peg3-Peg3, [Tetradecanoyl]-βAla-KEK-Peg3-Peg3, [Hexadecanoyl]-βAla-KEK-Peg3-Peg3, [Octadecanoyl]-βAla-KEK-Peg3-Peg3, [Eicosaenoyl]-βAla-KEK-Peg3-Peg3, [Dodecanoyl]-isoLys-KEK-Peg3-Peg3, [Tetradecanoyl]-isoLys-KEK-Peg3-Peg3, [Hexadecanoyl]-isoLys-KEK-Peg3-Peg3, [Octadecanoyl]-isoLys-KEK-Peg3-Peg3, [Eicosaenoyl]-isoLys-KEK-Peg3-Peg3, [Dodecanoyl]-[4-aminobutanoyl]-KEK-Peg3-Peg3, [Tetradecanoyl]-[4-aminobutanoyl]-KEK-Peg3-Peg3, [Hexadecanoyl]-[4-aminobutanoyl]-KEK-Peg3-Peg3, [Octadecanoyl]-[4-aminobutanoyl]-KEK-Peg3-Peg3, [Eicosaenoyl]-[4-aminobutanoyl]-KEK-Peg3-Peg3, [Dodecanoyl]-isoGlu-KEK-Peg3-Peg3-Peg3, [Tetradecanoyl]-isoGlu-KEK-Peg3-Peg3-Peg3, [Hexadecanoyl]-isoGlu-KEK-Peg3-Peg3-Peg3, [Octadecanoyl]-isoGlu-KEK-Peg3-Peg3-Peg3, [Eicosaenoyl]-isoGlu-KEK-Peg3-Peg3-Peg3, [Dodecanoyl]-βAla-KEK-Peg3-Peg3-Peg3, [Tetradecanoyl]-βAla-KEK-Peg3-Peg3-Peg3, [Hexadecanoyl]-βAla-KEK-Peg3-Peg3-Peg3, [Octadecanoyl]-βAla-KEK-Peg3-Peg3-Peg3, [Eicosaenoyl]-βAla-KEK-Peg3-Peg3-Peg3, [Dodecanoyl]-isoLys-KEK-Peg3-Peg3-Peg3, [Tetradecanoyl]-isoLys-KEK-Peg3-Peg3-Peg3, [Hexadecanoyl]-isoLys-KEK-Peg3-Peg3-Peg3, [Octadecanoyl]-isoLys-KEK-Peg3-Peg3-Peg3, [Eicosaenoyl]-isoLys-KEK-Peg3-Peg3-Peg3, [Dodecanoyl]-[4-aminobutanoyl]-KEK-Peg3-Peg3-Peg3, [Tetradecanoyl]-[4-aminobutanoyl]-KEK-Peg3-Peg3-Peg3, [Hexadecanoyl]-[4-aminobutanoyl]-KEK-Peg3-Peg3-Peg3, [Octadecanoyl]-[4-aminobutanoyl]-KEK-Peg3-Peg3-Peg3, [Eicosaenoyl]-[4-aminobutanoyl]-KEK-Peg3-Peg3-Peg3, [Dodecanoyl]-KEK-isoGlu-Peg3, [Tetradecanoyl]-KEK-isoGlu-Peg3, [Hexadecanoyl]-KEK-isoGlu-Peg3, [Octadecanoyl]-KEK-isoGlu-Peg3, [Eicosaenoyl]-KEK-isoGlu-Peg3, [Dodecanoyl]-KEK-βAla-Peg3, [Tetradecanoyl]-KEK-βAla-Peg3, [Hexadecanoyl]-KEK-βAla-Peg3, [Octadecanoyl]-KEK-βAla-Peg3, [Eicosaenoyl]-KEK-βAla-Peg3, [Dodecanoyl]-KEK-[4-aminobutanoyl]-PEG3, [Tetradecanoyl]-KEK-[4-aminobutanoyl]-PEG3, [Hexadecanoyl]-KEK-[4-aminobutanoyl]-PEG3, [Octadecanoyl]-KEK-[4-aminobutanoyl]-PEG3, [Eicosaenoyl]-KEK-[4-aminobutanoyl]-PEG3, [Dodecanoyl]-KEK-isoLys-Peg3, [Tetradecanoyl]-KEK-isoLys-Peg3, [Hexadecanoyl]-KEK-isoLys-Peg3, [Octadecanoyl]-KEK-isoLys-Peg3, [Eicosaenoyl]-KEK-isoLys-Peg3, [Dodecanoyl]-KEK-isoGlu-Peg3-Peg3, [Tetradecanoyl]-KEK-isoGlu-Peg3-Peg3, [Hexadecanoyl]-KEK-isoGlu-Peg3-Peg3, [Octadecanoyl]-KEK-isoGlu-Peg3-Peg3, [Eicosaenoyl]-KEK-isoGlu-Peg3-Peg3, [Dodecanoyl]-KEK-βAla-Peg3-Peg3, [Tetradecanoyl]-KEK-βAla-Peg3-Peg3, [Hexadecanoyl]-KEK-βAla-Peg3-Peg3, [Octadecanoyl]-KEK-βAla-Peg3-Peg3, [Eicosaenoyl]-βAla-KEK-Peg3-Peg3, [Dodecanoyl]-KEK-[4-aminobutanoyl]-Peg3-Peg3, [Tetradecanoyl]-KEK-[4-aminobutanoyl]-Peg3-Peg3, [Hexadecanoyl]-KEK-[4-aminobutanoyl]-Peg3-Peg3, [Octadecanoyl]-KEK-[4-aminobutanoyl]-Peg3-Peg3, [Eicosaenoyl]-KEK-[4-aminobutanoyl]-Peg3-Peg3, [Dodecanoyl]-KEK-isoLys-Peg3-Peg3, [Tetradecanoyl]-KEK-isoLys-Peg3-Peg3, [Hexadecanoyl]-KEK-isoLys-Peg3-Peg3, [Octadecanoyl]-KEK-isoLys-Peg3-Peg3, [Eicosaenoyl]-KEK-isoLys-Peg3-Peg3, [Dodecanoyl]-KEK-isoGlu-Peg3-Peg3-Peg3, [Tetradecanoyl]-KEK-isoGlu-Peg3-Peg3-Peg3, [Hexadecanoyl]-KEK-isoGlu-Peg3-Peg3-Peg3, [Octadecanoyl]-KEK-isoGlu-Peg3-Peg3-Peg3, [Eicosaenoyl]-KEK-isoGlu-Peg3-Peg3-Peg3, [Dodecanoyl]-KEK-βAla-Peg3-Peg3-Peg3, [Tetradecanoyl]KEK-βAla-Peg3-Peg3-Peg3, [Hexadecanoyl]-βAla-KEK-Peg3-Peg3-Peg3, [Octadecanoyl]-KEK-βAla-Peg3-Peg3-Peg3, [Eicosaenoyl]-KEK-βAla-Peg3-Peg3-Peg3, [Dodecanoyl]-KEK-[4-aminobutanoyl]-Peg3-Peg3-Peg3, [Tetradecanoyl]-KEK-[4-aminobutanoyl]-Peg3-Peg3-Peg3, [Hexadecanoyl]-KEK-[4-aminobutanoyl]-Peg3-Peg3-Peg3, [Octadecanoyl]-KEK-[4-aminobutanoyl]-Peg3-Peg3-Peg3, [Eicosaenoyl]-KEK-[4-aminobutanoyl]-Peg3-Peg3-Peg3, [Dodecanoyl]-KEK-isoLys-Peg3-Peg3-Peg3, [Tetradecanoyl]-KEK-isoLys-Peg3-Peg3-Peg3, [Hexadecanoyl]-KEK-isoLys-Peg3-Peg3-Peg3, [Octadecanoyl]-KEK-isoLys-Peg3-Peg3-Peg3, [Eicosaenoyl]-KEK-isoLys-Peg3-Peg3-Peg3, [13-carboxy-tridecanoyl]-isoGlu, [15-carboxy-pentadecanoyl]-isoGlu, [17-carboxy-heptadecanoyl]-isoGlu, [19-carboxy-nonadecanoyl]-isoGlu, [21-carboxy-hen21-carboxy-heneicosanoyl]-isoGlu, [17-Carboxy-heptadecanoyl]-βAla, [19-Carboxy-nonadecanoyl]-βAla, [21-Carboxy-heneicosanoyl]-βAla, [15-Carboxy-pentadecanoyl]-βAla, [13-Carboxy-tridecanoyl]-βAla, [13-Carboxy-tridecanoyl]-isoLys, [15-Carboxy-pentadecanoyl]-isoLys, [17-Carboxy-heptadecanoyl]-isoLys, [19-Carboxy-nonadecanoyl]-isoLys, [21-Carboxy-heneicosanoyl]-isoLys, [17-Carboxy-heptadecanoyl]-[4-aminobutanoyl], [19-Carboxy-nonadecanoyl]-[4-aminobutanoyl], [21-Carboxy-heneicosayl]-[4-aminobutanoyl], [15-Carboxy-pentadecanoyl]-[4-aminobutanoyl], [13-Carboxy-tridecanoyl]-[4-aminobutanoyl], [17-Carboxyheptadecanoyl]-KEK, [19-Carboxynonadecanoyl]-KEK, [21-Carboxyheneicosanoyl]-KEK, [15-Carboxypentadecanoyl]-KEK, [13-Carboxytridecanoyl]-KEK, [13-Carboxy-tridecanoyl]-Peg3, [15-Carboxy-pentadecanoyl]-Peg3, [17-Carboxy-heptadecanoyl]-Peg3, [19-Carboxy-nonadecanoyl]-Peg3, [21-Carboxy-heneicosanoyl]-Peg3, [13-carboxy-tridecanoyl]-Peg3-Peg3, [15-carboxy-pentadecanoyl]-Peg3-Peg3, [17-Carboxyheptadecanoyl]-Peg3-Peg3, [19-Carboxynonadecanoyl]-Peg3- Peg3, [21-carboxy-heneicosanoyl]-Peg3-Peg3, [13-carboxy-tridecanoyl]-Peg3-Peg3-Peg3, [15-carboxy-pentadecanoyl]-Peg3-Peg3-Peg3, [17-carboxy-heptadecanoyl]-Peg3-Peg3-Peg3, [19-carboxy-nonadecanoyl]-Peg3-Peg3-Peg3, [21-carboxy-heneicosanoyl]-Peg3-Peg3-Peg3, [13-Carboxy-tridecanoyl]-isoGlu-Peg3, [15-Carboxy-pentadecanoyl]-isoGlu-Peg3, [17-Carboxy-heptadecanoyl]-isoGlu-Peg3, [19-Carboxy-nonadecanoyl]-isoGlu-Peg3, [21-Carboxy-heneicosanoyl]-isoGlu-Peg3, [13-Carboxy-tridecanoyl]-βAla-Peg3, [15-Carboxy-pentadecanoyl]-βAla-Peg3, [17-Carboxy-heptadecanoyl]-βAla-Peg3, [19-Carboxy-nonadecanoyl]-βAla-Peg3, [21-Carboxy-heneicosanoyl]-βAla-Peg3, [13-Carboxy-tridecanoyl]-isoLys-Peg3, [15-Carboxy-pentadecanoyl]-isoLys-Peg3, [17-Carboxy-heptadecanoyl]-isoLys-Peg3, [19-Carboxy-nonadecanoyl]-isoLys-Peg3, [21-Carboxy-heneicosanoyl]-isoLys-Peg3, [13-Carboxy-tridecanoyl]-[4-aminobutanoyl]-Peg3, [15-Carboxy-pentadecanoyl]-[4-aminobutanoyl]-Peg3, [17-Carboxy-heptadecanoyl]-[4-aminobutanoyl]-Peg3, [19-Carboxy-nonadecanoyl]-[4-aminobutanoyl]-Peg3, [21-Carboxy-heneicosayl]-[4-aminobutanoyl]-Peg3, [13-Carboxy-tridecanoyl]-KEK-Peg3, [15-Carboxy-pentadecanoyl]-KEK-Peg3, [17-Carboxy-heptadecanoyl]-KEK-Peg3, [19-Carboxy-nonadecanoyl]-KEK-Peg3, [21-Carboxy-heneicosanoyl]-KEK-Peg3, [13-carboxy-tridecanoyl]-isoGlu-Peg3-Peg3, [15-carboxy-pentadecanoyl]-isoGlu-Peg3-Peg3, [17-carboxy-heptadecanoyl]-isoGlu-Peg3-Peg3, [19-carboxy-nonadecanoyl]-isoGlu-Peg3-Peg3, [21-carboxy-heneicosanoyl]-isoGlu-Peg3-Peg3, [13-Carboxy-tridecanoyl]-βAla-Peg3-Peg3, [15-Carboxy-pentadecanoyl]-βAla-Peg3-Peg3, [17-Carboxy-heptadecanoyl]-βAla-Peg3-Peg3, [19-Carboxy-nonadecanoyl]-βAla-Peg3-Peg3, [21-Carboxy-heneicosanoyl]-βAla-Peg3-Peg3, [13-Carboxy-tridecanoyl]-isoLys-Peg3-Peg3, [15-Carboxy-pentadecanoyl]-isoLys-Peg3-Peg3, [17-Carboxy-heptadecanoyl]-isoLys-Peg3-Peg3, [19-Carboxy-nonadecanoyl]-isoLys-Peg3-Peg3, [21-Carboxy-heneicosanoyl]-isoLys-Peg3-Peg3, [13-Carboxy-tridecanoyl]-[4-aminobutanoyl]-Peg3-Peg3, [15-Carboxy-pentadecanoyl]-[4-aminobutanoyl]-Peg3-Peg3, [17-Carboxy-heptadecanoyl]-[4-aminobutanoyl]-Peg3-Peg3, [19-Carboxy-nonadecanoyl]-[4-aminobutanoyl]-Peg3-Peg3, [21-Carboxy-heneicosayl]-[4-aminobutanoyl]-Peg3-Peg3, [13-Carboxy-tridecanoyl]-KEK-Peg3-Peg3, [15-Carboxy-pentadecanoyl]-KEK-Peg3-Peg3, [17-Carboxy-heptadecanoyl]-KEK-Peg3-Peg3, [19-Carboxy-nonadecanoyl]-KEK-Peg3-Peg3, [21-Carboxy-heneicosanoyl]-KEK-Peg3-Peg3, [13-carboxy-tridecanoyl]-isoGlu-Peg3-Peg3-Peg3, [15-carboxy-pentadecanoyl]-isoGlu-Peg3-Peg3-Peg3, [17-carboxy-heptadecanoyl]-isoGlu-Peg3-Peg3-Peg3, [19-carboxy-nonadecanoyl]-isoGlu-Peg3-Peg3-Peg3, [21-carboxy-heneicosanoyl]-isoGlu-Peg3-Peg3-Peg3, [13-Carboxy-tridecanoyl]-βAla-Peg3-Peg3-Peg3, [15-Carboxy-pentadecanoyl]-βAla-Peg3-Peg3-Peg3, [17-Carboxy-heptadecanoyl]-βAla-Peg3-Peg3-Peg3, [19-Carboxy-nonadecanoyl]-βAla-Peg3-Peg3-Peg3, [21-Carboxy-heneicosanoyl]-βAla-Peg3-Peg3-Peg3, [13-carboxy-tridecanoyl]-isoLys-Peg3-Peg3-Peg3, [15-carboxy-pentadecanoyl]-isoLys-Peg3-Peg3-Peg3, [17-carboxy-heptadecanoyl]-isoLys-Peg3-Peg3-Peg3, [19-carboxy-nonadecanoyl]-isoLys-Peg3-Peg3-Peg3, [21-carboxy-heneicosanoyl]-isoLys-Peg3-Peg3-Peg3, [13-Carboxy-tridecanoyl]-[4-aminobutanoyl]-Peg3-Peg3-Peg3, [15-Carboxy-pentadecanoyl]-[4-aminobutanoyl]-Peg3-Peg3-Peg3, [17-Carboxy-heptadecanoyl]-[4-aminobutanoyl]-Peg3-Peg3-Peg3, [19-Carboxy-nonadecanoyl]-[4-aminobutanoyl]-Peg3-Peg3-Peg3, [21-Carboxy-heneicosanoyl]-[4-aminobutanoyl]-Peg3-Peg3-Peg3, [13-Carboxy-tridecanoyl]-KEK-Peg3-Peg3-Peg3, [15-Carboxy-pentadecanoyl]-KEK-Peg3-Peg3-Peg3, [17-Carboxy-heptadecanoyl]-KEK-Peg3-Peg3-Peg3, [19-Carboxy-nonadecanoyl]-KEK-Peg3-Peg3-Peg3, [21-Carboxy-heneicosanoyl]-KEK-Peg3-Peg3-Peg3, [13-Carboxy-tridecanoyl]-isoGlu-KEK-Peg3, [15-Carboxy-pentadecanoyl]-isoGlu-KEK-Peg3, [17-Carboxy-heptadecanoyl]-isoGlu-KEK-Peg3, [19-Carboxy-nonadecanoyl]-isoGlu-KEK-Peg3, [21-Carboxy-heneicosanoyl]-isoGlu-KEK-Peg3, [13-Carboxy-tridecanoyl]-[4-aminobutanoyl]-KEK-Peg3, [15-Carboxy-pentadecanoyl]-[4-aminobutanoyl]-KEK-Peg3, [17-Carboxy-heptadecanoyl]-[4-aminobutanoyl]-KEK-Peg3, [19-Carboxy-nonadecanoyl]-[4-aminobutanoyl]-KEK-Peg3, [21-Carboxy-heneicosaenoyl]-[4-aminobutanoyl]-KEK-Peg3, [13-Carboxy-tridecanoyl]-isoLys-KEK-Peg3, [15-Carboxy-pentadecanoyl]-isoLys-KEK-Peg3, [17-Carboxy-heptadecanoyl]-isoLys-KEK-Peg3, [19-Carboxy-nonadecanoyl]-isoLys-KEK-Peg3, [21-Carboxy-heneicosanoyl]-isoLys-KEK-Peg3, [13-Carboxy-tridecanoyl]-βAla-KEK-Peg3, [15-Carboxy-pentadecanoyl]-βAla-KEK-Peg3, [17-Carboxy-heptadecanoyl]-βAla-KEK-Peg3, [19-Carboxy-nonadecanoyl]-βAla-KEK-Peg3, [21-Carboxy-heneicosanoyl]-βAla-KEK-Peg3, [13-Carboxy-tridecanoyl]-isoGlu-KEK-Peg3-Peg3, [15-Carboxy-pentadecanoyl]-isoGlu-KEK-Peg3-Peg3, [17-Carboxy-heptadecanoyl]-isoGlu-KEK-Peg3-Peg3, [19-Carboxy-nonadecanoyl]-isoGlu-KEK-Peg3-Peg3, [21-Carboxy-heneicosanoyl]-isoGlu-KEK-Peg3-Peg3, [13-Carboxy-tridecanoyl]-βAla-KEK-Peg3-Peg3, [15-Carboxy-pentadecanoyl]-βAla-KEK-Peg3-Peg3, [17-Carboxy-heptadecanoyl]-βAla-KEK-Peg3-Peg3, [19-Carboxy-nonadecanoyl]-βAla-KEK-Peg3-Peg3, [21-Carboxy-heneicosanoyl]-βAla-KEK-Peg3-Peg3, [13-Carboxy-tridecanoyl]-isoLys-KEK-Peg3-Peg3, [15-Carboxy-pentadecanoyl]-isoLys-KEK-Peg3-Peg3, [17-Carboxy-heptadecanoyl]-isoLys-KEK-Peg3-Peg3, [19-Carboxy-nonadecanoyl]-isoLys-KEK-Peg3-Peg3, [21-Carboxy-heneicosanoyl]-isoLys-KEK-Peg3-Peg3, [13-Carboxy-tridecanoyl]-[4-aminobutanoyl]-KEK-Peg3-Peg3, [15-Carboxy-pentadecanoyl]-[4-aminobutanoyl]-KEK-Peg3-Peg3, [17-Carboxy-heptadecanoyl]-[4-aminobutanoyl]-KEK-Peg3-Peg3, [19-Carboxy-nonadecanoyl]-[4-aminobutanoyl]-KEK-Peg3-Peg3, [21-Carboxy-heneicosanoyl]-[4-aminobutanoyl]-KEK-Peg3-Peg3, [13-Carboxy-tridecanoyl]-isoGlu-KEK-Peg3-Peg3-Peg3, [15-Carboxy-pentadecanoyl]-isoGlu-KEK-Peg3-Peg3-Peg3, [17-Carboxy-heptadecanoyl]-isoGlu-KEK-Peg3-Peg3-Peg3, [19-Carboxy-nonadecanoyl]-isoGlu-KEK-Peg3-Peg3-Peg3, [21-Carboxy-heneicosanoyl]-isoGlu-KEK-Peg3-Peg3-Peg3, [13-Carboxy-tridecanoyl]-βAla-KEK-Peg3-Peg3-Peg3, [15-Carboxy-pentadecanoyl]-βAla-KEK-Peg3-Peg3-Peg3, [17-Carboxy-heptadecanoyl]-βAla-KEK-Peg3-Peg3-Peg3, [19-Carboxy-nonadecanoyl]-βAla-KEK-Peg3-Peg3-Peg3, [21-Carboxy-heneicosanoyl]-βAla-KEK-Peg3-Peg3-Peg3, [13-Carboxy-tridecanoyl]-isoLys-KEK-Peg3-Peg3-Peg3, [15-Carboxy-pentadecanoyl]-isoLys-KEK-Peg3-Peg3-Peg3, [17-Carboxy-heptadecanoyl]-isoLys-KEK-Peg3-Peg3-Peg3, [19-Carboxy-nonadecanoyl]-isoLys-KEK-Peg3-Peg3-Peg3, [21-Carboxy-heneicosanoyl]-isoLys-KEK-Peg3-Peg3-Peg3, [13-Carboxy-tridecanoyl]-[4-aminobutanoyl]-KEK-Peg3-Peg3-Peg3, [15-Carboxy-pentadecanoyl]-[4-aminobutanoyl]-KEK-Peg3-Peg3-Peg3, [17-Carboxy-heptadecanoyl]-[4-aminobutanoyl]-KEK-Peg3-Peg3-Peg3, [19-Carboxy-nonadecanoyl]-[4-aminobutanoyl]-KEK-Peg3-Peg3-Peg3, [21-Carboxy-heneicosanoyl]-[4-aminobutanoyl]-KEK-Peg3-Peg3-Peg3, [13-Carboxy-tridecanoyl]-KEK-isoGlu-Peg3, [15-Carboxy-pentadecanoyl]-KEK-isoGlu-Peg3, [17-Carboxy-heptadecanoyl]-KEK-isoGlu-Peg3, [19-Carboxy-nonadecanoyl]-KEK-isoGlu-Peg3, [21-Carboxy-heneicosanoyl]-KEK-isoGlu-Peg3, [13-Carboxy-tridecanoyl]-KEK-βAla-Peg3, [15-Carboxy-pentadecanoyl]-KEK-βAla-Peg3, [17-Carboxy-heptadecanoyl]-KEK-βAla-Peg3, [19-Carboxy-nonadecanoyl]-KEK-βAla-Peg3, [21-Carboxy-heneicosanoyl]-KEK-βAla-Peg3, [13-Carboxy-tridecanoyl]-KEK-[4-aminobutanoyl]-Peg3, [15-Carboxy-pentadecanoyl]-KEK-[4-aminobutanoyl]-Peg3, [17-Carboxy-heptadecanoyl]-KEK-[4-aminobutanoyl]-Peg3, [19-Carboxy-nonadecanoyl]-KEK-[4-aminobutanoyl]-Peg3, [21-Carboxy-heneicosaenoyl]-KEK-[4-aminobutanoyl]-Peg3, [13-Carboxy-tridecanoyl]-KEK-isoLys-Peg3, [15-Carboxy-pentadecanoyl]-KEK-isoLys-Peg3, [17-Carboxy-heptadecanoyl]-KEK-isoLys-Peg3, [19-Carboxy-nonadecanoyl]-KEK-isoLys-Peg3, [21-Carboxy-heneicosanoyl]-KEK-isoLys-Peg3, [13-Carboxy-tridecanoyl]-KEK-isoGlu-Peg3-Peg3, [15-Carboxy-pentadecanoyl]-KEK-isoGlu-Peg3-Peg3, [17-Carboxy-heptadecanoyl]-KEK-isoGlu-Peg3-Peg3, [19-Carboxy-nonadecanoyl]-KEK-isoGlu-Peg3-Peg3, [21-Carboxy-heneicosanoyl]-KEK-isoGlu-Peg3-Peg3, [13-Carboxy-tridecanoyl]-KEK-βAla-Peg3-Peg3, [15-Carboxy-pentadecanoyl]-KEK-βAla-Peg3-Peg3, [17-Carboxy-heptadecanoyl]-KEK-βAla-Peg3-Peg3, [19-Carboxy-nonadecanoyl]-KEK-βAla-Peg3-Peg3, [21-Carboxy-heneicosanoyl]-βAla-KEK-Peg3-Peg3, [13-Carboxy-tridecanoyl]-KEK-[4-aminobutanoyl]-Peg3-Peg3, [15-Carboxy-pentadecanoyl]-KEK-[4-aminobutanoyl]-Peg3-Peg3, [17-Carboxy-heptadecanoyl]-KEK-[4-aminobutanoyl]-Peg3-Peg3, [19-Carboxy-nonadecanoyl]-KEK-[4-aminobutanoyl]-Peg3-Peg3, [21-Carboxy-heneicosaenoyl]-KEK-[4-aminobutanoyl]-Peg3-Peg3, [13-Carboxy-tridecanoyl]-KEK-isoLys-Peg3-Peg3, [15-Carboxy-pentadecanoyl]-KEK-isoLys-Peg3-Peg3, [17-Carboxy-heptadecanoyl]-KEK-isoLys-Peg3-Peg3, [19-Carboxy-nonadecanoyl]-KEK-isoLys-Peg3-Peg3, [21-Carboxy-heneicosanoyl]-KEK-isoLys-Peg3-Peg3, [13-Carboxy-tridecanoyl]-KEK-isoGlu-Peg3-Peg3-Peg3, [15-Carboxy-pentadecanoyl]-KEK-isoGlu-Peg3-Peg3-Peg3, [17-Carboxy-heptadecanoyl]-KEK-isoGlu-Peg3-Peg3-Peg3, [19-Carboxy-nonadecanoyl]-KEK-isoGlu-Peg3-Peg3-Peg3, [21-Carboxy-heneicosanoyl]-KEK-isoGlu-Peg3-Peg3-Peg3, [13-Carboxy-tridecanoyl]-KEK-βAla-Peg3-Peg3-Peg3, [15-Carboxy-pentadecanoyl]KEK-βAla-Peg3-Peg3-Peg3, [17-Carboxy-heptadecanoyl]-βAla-KEK-Peg3-Peg3-Peg3, [19-Carboxy-nonadecanoyl]-KEK-βAla-Peg3-Peg3-Peg3, [21-Carboxy-heneicosanoyl]-KEK-βAla-Peg3-Peg3-Peg3, [13-Carboxy-tridecanoyl]-KEK-[4-aminobutanoyl]-Peg3-Peg3-Peg3, [15-Carboxy-pentadecanoyl]-KEK-[4-aminobutanoyl]-Peg3-Peg3-Peg3, [17-Carboxy-heptadecanoyl]-KEK-[4-aminobutanoyl]-Peg3-Peg3-Peg3, [19-Carboxy-nonadecanoyl]-KEK-[4-aminobutanoyl]-Peg3-Peg3-Peg3, [21-Carboxy-heneicosanoyl]-KEK-[4-aminobutanoyl]-Peg3-Peg3-Peg3, [13-Carboxy-tridecanoyl]-KEK-isoLys-Peg3-Peg3-Peg3, [15-Carboxy-pentadecanoyl]-KEK-isoLys-Peg3-Peg3-Peg3, [17-Carboxy-heptadecanoyl]-KEK-isoLys-Peg3-Peg3-Peg3, [19-Carboxy-nonadecanoyl]-KEK-isoLys-Peg3-Peg3-Peg3, [21-Carboxy-heneicosanoyl]-KEK-isoLys-Peg3-Peg3-Peg3.

[0133] Specific preferred substituent Z 1 - and Z 1 -Z 2 -The following are some examples: [Hexadecanoyl], [Octadecanoyl], [17-Carboxy-heptadecanoyl], [19-Carboxy-nonadecanoyl], [Hexadecanoyl]-isoGlu, [Octadecanoyl]-isoGlu, [Hexadecanoyl]-βAla, [Octadecanoyl]-βAla, [Hexadecanoyl]-isoGlu-Peg3, [Hexadecanoyl]-βAla-Peg3, [Hexadecanoyl]-isoGlu-Peg3-Peg3, [Hexadecanoyl]-βAla-Peg3-Peg3, [Hexadecanoyl]-βAla-Peg3-Peg3-Peg3, [Hexadecanoyl]-isoLys, [Hexadecanoyl]-[4-aminobutanoyl], [Hexadecanoyl]-isoLys-Peg3, [Hexadecanoyl]-[4-aminobutanoyl]-PEG3, [Hexadecanoyl]-isoLys-Peg3-Peg3, [Hexadecanoyl]-[4-aminobutanoyl]-Peg3-Peg3, [Hexadecanoyl]-isoLys-Peg3-Peg3-Peg3, [Hexadecanoyl]-[4-aminobutanoyl]-Peg3-Peg3-Peg3, [17-carboxyheptadecanoyl]-isoGlu, [19-carboxy-nonadecanoyl]-isoGlu, [17-carboxy-heptadecanoyl]-βAla, [19-Carboxy-nonadecanoyl]-βAla, [17-carboxyheptadecanoyl]-isoGlu-Peg3, [19-carboxy-nonadecanoyl]-isoGlu-Peg3, [17-carboxyheptadecanoyl]-βAla-Peg3, [19-Carboxy-nonadecanoyl]-βAla-Peg3, [17-carboxyheptadecanoyl]-isoGlu-Peg3-Peg3, [19-carboxy-nonadecanoyl]-isoGlu-Peg3-Peg3, [17-carboxy-heptadecanoyl]-βAla-Peg3-Peg3, [19-carboxy-nonadecanoyl]-βAla-Peg3-Peg3, [17-carboxyheptadecanoyl]-isoGlu-Peg3-Peg3-Peg3, [19-carboxy-nonadecanoyl]-isoGlu-Peg3-Peg3-Peg3, [17-carboxyheptadecanoyl]-βAla-Peg3-Peg3-Peg3, [19-carboxy-nonadecanoyl]-βAla-Peg3-Peg3-Peg3, [17-carboxyheptadecanoyl]-isoLys, [19-carboxy-nonadecanoyl]-isoLys, [17-Carboxyheptadecanoyl]-[4-aminobutanoyl], [19-Carboxy-nonadecanoyl]-[4-aminobutanoyl], [17-carboxyheptadecanoyl]-isoLys-Peg3, [19-carboxy-nonadecanoyl]-isoLys-Peg3, [17-Carboxyheptadecanoyl]-[4-aminobutanoyl]-PEG3, [19-Carboxy-nonadecanoyl]-[4-aminobutanoyl]-PEG3, [17-carboxyheptadecanoyl]-isoLys-Peg3-Peg3, [19-carboxy-nonadecanoyl]-isoLys-Peg3-Peg3, [17-carboxy-heptadecanoyl]-[4-aminobutanoyl]-PEG3-PEG3, [19-Carboxy-nonadecanoyl]-[4-aminobutanoyl]-Peg3-Peg3, [17-carboxyheptadecanoyl]-isoLys-Peg3-Peg3-Peg3, [19-carboxy-nonadecanoyl]-isoLys-Peg3-Peg3-Peg3, [17-carboxyheptadecanoyl]-[4-aminobutanoyl]-Peg3-Peg3-Peg3, [19-Carboxy-nonadecanoyl]-[4-aminobutanoyl]-Peg3-Peg3-Peg3.

[0134] More preferred substituent Z 1 -Z 2 -The following are some examples: [Hexadecanoyl]-isoGlu, [Hexadecanoyl]-βAla, [Hexadecanoyl]-isoGlu-Peg3, [Hexadecanoyl]-βAla-Peg3, [Hexadecanoyl]-isoGlu-Peg3-Peg3, [Hexadecanoyl]-isoLys, [Hexadecanoyl]-isoLys-Peg3, [Hexadecanoyl]-isoLys-Peg3-Peg3, [17-carboxyheptadecanoyl]-isoGlu, [19-carboxy-nonadecanoyl]-isoGlu, [17-carboxyheptadecanoyl]-isoGlu-Peg3, [19-carboxy-nonadecanoyl]-isoGlu-Peg3, [17-carboxyheptadecanoyl]-isoGlu-Peg3-Peg3, [19-carboxy-nonadecanoyl]-isoGlu-Peg3-Peg3, [17-carboxyheptadecanoyl]-isoGlu-Peg3-Peg3-Peg3, [19-carboxy-nonadecanoyl]-isoGlu-Peg3-Peg3-Peg3, [17-carboxyheptadecanoyl]-isoLys, [19-carboxy-nonadecanoyl]-isoLys, [17-carboxyheptadecanoyl]-isoLys-Peg3, [19-carboxy-nonadecanoyl]-isoLys-Peg3, [17-carboxyheptadecanoyl]-isoLys-Peg3-Peg3, [19-carboxy-nonadecanoyl]-isoLys-Peg3-Peg3, [17-carboxyheptadecanoyl]-isoLys-Peg3-Peg3-Peg3, [19-carboxy-nonadecanoyl]-isoLys-Peg3-Peg3-Peg3.

[0135] A more preferred substituent Z 1 -Z 2 -The following are some examples: [Hexadecanoyl]-KEK, [Octadecanoyl]-KEK, [Hexadecanoyl]-βAla-Peg3, [Hexadecanoil]-KEK-Peg3, [Hexadecanoyl]-KEK-Peg3-Peg3, [Hexadecanoyl]-KEK-Peg3-Peg3-Peg3, [17-carboxyheptadecanoyl]-KEK, [19-carboxy-nonadecanoyl]-KEK, [17-carboxyheptadecanoyl]-KEK-Peg3, [19-carboxy-nonadecanoyl]-KEK-Peg3, [17-carboxyheptadecanoyl]-KEK-Peg3-Peg3, [19-carboxy-nonadecanoyl]-KEK-Peg3-Peg3, [17-carboxyheptadecanoyl]-isoGlu-KEK [19-carboxy-nonadecanoyl]-isoGlu-KEK, [17-carboxyheptadecanoyl]-isoLys-KEK [19-carboxy-nonadecanoyl]-isoLys-KEK, [17-Carboxyheptadecanoyl]-βAla-KEK [19-Carboxy-nonadecanoyl]-βAla-KEK, [17-Carboxy-heptadecanoyl]-KEK-Peg3-Peg3-Peg3, [19-carboxy-nonadecanoyl]-KEK-Peg3-Peg3-Peg3, [17-Carboxyheptadecanoyl]-[4-aminobutanoyl]-KEK, [19-Carboxy-nonadecanoyl]-[4-aminobutanoyl]-KEK, [17-Carboxyheptadecanoyl]-[4-aminobutanoyl]-KEK-Peg3-Peg3-Peg3, [19-Carboxy-nonadecanoyl]-[4-aminobutanoyl]-KEK-Peg3-Peg3-Peg3, [17-Carboxyheptadecanoyl]-[4-aminobutanoyl]-KEK-Peg3-Peg3, [19-Carboxy-nonadecanoyl]-[4-aminobutanoyl]-KEK-Peg3-Peg3, [Hexadecanoyl]-isoGlu-KEK-Peg3 [Hexadecanoyl]-isoGlu-KEK-Peg3-Peg3, [19-carboxy-nonadecanoyl]-isoGlu-KEK, [19-Carboxy-nonadecanoyl]-[4-aminobutanoyl]-KEK, [17-Carboxyheptadecanoyl]-[4-aminobutanoyl]-KEK-Peg3-Peg3-Peg3, [17-Carboxyheptadecanoyl]-[4-aminobutanoyl]-KEK-Peg3-Peg3, [19-Carboxy-nonadecanoyl]-[4-aminobutanoyl]-KEK-Peg3-Peg3, [17-carboxyheptadecanoyl]-KEK-Peg3-Peg3, [19-carboxy-nonadecanoyl]-KEK-Peg3-Peg3, [17-carboxyheptadecanoyl]-isoGlu-KEK-Peg3, [19-carboxy-nonadecanoyl]-isoGlu-KEK-Peg3, [17-carboxyheptadecanoyl]-isoGlu-KEK-Peg3-Peg3, [19-carboxy-nonadecanoyl]-isoGlu-KEK-Peg3-Peg3.

[0136] Examples of Ψ containing amino acid side chains and various substituents (fatty acids, FA) optionally conjugated by spacers are shown below: [ka] JPEG0007860224000002.jpg234169JPEG0007860224000003.jpg101169JPEG0007860224000004.jpg239165JPEG0007860224000005.jpg204165

[0137] Furthermore, the following are examples of substituents [hexadecanoyl]-isoGlu that are conjugated to the side chain of the lysine residue: [ka]

[0138] Therefore, the side chain of the Lys residue is connected to the isoGlu spacer -Z2-(-Z) via an amide bond. S1 It is covalently bonded to the side chain carboxyl group of (Z). 1 ) is covalently bonded to the amino group of the isoGlu spacer via an amide bond.

[0139] Examples of substituents [hexadecanoyl]-[4-aminobutanoyl] conjugated with the side chain of a lysine residue are shown below. [ka]

[0140] Examples of substituents [(hexadecanoyl)iso-Lys] conjugated with the side chain of a lysine residue are shown below. [ka]

[0141] Examples of substituents [(hexadecanoyl)β-Ala] conjugated to the side chain of a lysine residue are given below. [ka]

[0142] -Z 2 -Z 1 Some further specific examples of these combinations are shown below. In each example, --- indicates the binding site with the side chain of the amino acid component of Ψ: [ka] JPEG0007860224000011.jpg166133

[0143] Those skilled in the art will be well aware of appropriate techniques for preparing substituents to be used in the context of the present invention and for conjugating them with appropriate amino acid side chains in a double agonist peptide. For appropriate chemistry examples, see WO98 / 08871, WO00 / 55184, WO00 / 55119, Madsen et al., J. Med. Chem. 50:6126-32 (2007), and Knudsen et al., J. Med. Chem. 43:1664-1669 (2000), which are incorporated herein by reference.

[0144] c. Synthesis of double agonists The dual agonists of the present invention are preferably synthesized by solid-phase or liquid-phase peptide synthesis methods. In this context, refer to WO98 / 11125 and, in particular, Fields, GB et al., 2002, "Principles and practice of solid-phase peptide synthesis". In: Synthetic Peptides (2nd Edition), as well as the examples herein.

[0145] In the present invention, the dual agonist of the present invention is, for example, (a) A step of synthesizing a biagonal agonist by a solid-phase or liquid-phase peptide synthesis method and recovering the synthesized biagonal agonist thus obtained, (b) The step of expressing a precursor peptide sequence from a nucleic acid construct encoding the precursor peptide, recovering the expression product, and modifying the precursor peptide to obtain the compound of the present invention. It can be synthesized or produced by several methods, including methods that include [the specified element].

[0146] The precursor peptide includes one or more non-proteogenic amino acids, such as Aib, Orn, Dap, or Dab, and a lipophilic substituent Z at residue Ψ. 1 or Z 1 -Z 2 - Introduction, appropriate terminal base R 1 and R 2 It can be modified by introducing, for example, [something].

[0147] Expression is typically carried out from nucleic acids encoding the precursor peptide and can be performed in cell- or cell-free expression systems containing such nucleic acids.

[0148] The analogues of the present invention are preferably synthesized by solid-phase or liquid-phase peptide synthesis. In this context, refer to WO98 / 11125 and, in particular, Fields, GB et al., 2002, "Principles and practice of solid-phase peptide synthesis". In: Synthetic Peptides (2nd Edition), and the examples herein.

[0149] Recombinant expression typically involves inserting a nucleic acid fragment encoding a precursor peptide into a suitable vector to form a cloning or expression vector. Depending on the purpose and type of application, the vector can be in the form of a plasmid, phage, cosmid, minichromosome, or virus, although naked DNA, which is transiently expressed only in specific cells, is also an important vector. Preferred cloning and expression vectors (plasmid vectors) are capable of autonomous replication and therefore allow for high copy numbers for the purpose of high-level expression or high-level replication for subsequent cloning.

[0150] In general terms, an expression vector comprises the following features in a 5'→3' oriented and operable ligation: a promoter to drive the expression of a nucleic acid fragment; a nucleic acid sequence encoding a leader peptide that enables optional secretion (into the extracellular phase or, where applicable, into the periplasm); a nucleic acid fragment encoding a precursor peptide; and a nucleic acid sequence encoding an optional terminator. These may include additional features such as selection markers and origins of replication. When manipulating with an expression vector in a production strain or cell line, it may be preferable that the vector be able to be integrated into the host cell genome. Those skilled in the art are very familiar with suitable vectors and can design them according to their specific requirements.

[0151] The vector of the present invention is used to transform host cells to produce precursor peptides. Such transformed cells may be cultured cells or cell lines used for the proliferation of nucleic acid fragments and vectors, and / or for the recombinant production of precursor peptides.

[0152] Preferred transformed cells are microorganisms such as bacteria [species of the genera Escherichia (e.g., Escherichia coli), Bacillus (e.g., Bacillus subtilis), Salmonella, or Mycobacterium (preferably non-pathogenic, e.g., bovine Mycobacterium BCG)], yeasts (e.g., budding yeast and Pichia pastris), and protozoa. Alternatively, transformed cells may originate from multicellular organisms, i.e., they may be animal cells such as fungal cells, insect cells, algal cells, plant cells, or mammalian cells. For the purpose of cloning and / or optimized expression, it is preferable that the transformed cells can replicate the nucleic acid fragments of the present invention. Cells expressing the nucleic acid fragments can be used for small-scale or large-scale preparation of the peptides of the present invention.

[0153] When generating precursor peptides using transformed cells, it is not strictly necessary, but it is advantageous for the expression product to be secreted into the culture medium.

[0154] d. Pharmaceutical compositions One aspect of the present invention relates to a composition comprising a dual agonist according to the present invention, or a pharmaceutically acceptable salt or solvate thereof, together with a carrier. In one embodiment of the present invention, the composition is a pharmaceutical composition, and the carrier is a pharmaceutically acceptable carrier. The present invention also relates to a pharmaceutical composition comprising a dual agonist according to the present invention, or a salt or solvate thereof, together with a carrier, excipient, or vehicle. Accordingly, the dual agonist according to the present invention, or a salt or solvate thereof, in particular a pharmaceutically acceptable salt or solvate thereof, may be prepared for storage or administration and formulated as a composition or pharmaceutical composition comprising a therapeutically effective amount of the dual agonist according to the present invention, or a salt or solvate thereof.

[0155] Suitable salts formed using a base include metal salts such as alkali metal or alkaline earth metal salts, e.g., sodium, potassium, or magnesium salts; ammonia salts and organic amine salts, e.g., morpholine, thiomorpholine, piperidine, pyrrolidine, lower mono-, di-, or tri-alkylamines (e.g., ethyl-tert-butyl-, diethyl-, diisopropyl-, triethyl-, tributyl-, or dimethylpropylamine), or lower mono-, di-, or tri-(hydroxyalkyl)amines (e.g., mono-, di-, or triethanolamine). Internal salts can also be formed. Similarly, if the compound of the present invention contains a basic moiety, a salt can be formed using an organic or inorganic acid. For example, salts can be formed from the following acids, namely formic acid, acetic acid, propionic acid, butyric acid, valeric acid, caproic acid, oxalic acid, lactic acid, citric acid, tartaric acid, succinic acid, fumaric acid, maleic acid, malonic acid, mandelic acid, malic acid, phthalic acid, hydrochloric acid, hydrobromic acid, phosphoric acid, nitric acid, sulfuric acid, benzoic acid, carbonic acid, uric acid, methanesulfonic acid, naphthalenesulfonic acid, benzenesulfonic acid, toluenesulfonic acid, p-toluenesulfonic acid (i.e., 4-methylbenzenesulfonic acid), camphorsulfonic acid, 2-aminoethanesulfonic acid, aminomethylphosphonic acid, and trifluoromethanesulfonic acid (the latter also known as triflic acid), as well as other known pharmaceutically acceptable acids. Amino acid addition salts can also be formed using amino acids, such as lysine, glycine, or phenylalanine.

[0156] In one embodiment, the pharmaceutical composition of the present invention is in the form of a pharmaceutically acceptable acid addition salt in which the double agonist is located.

[0157] In some embodiments, the pharmaceutical composition of the present invention is formulated as a 1 mL solution for injection.

[0158] e. Titrate and therapeutic dose The dose may be a titration dose or a therapeutic dose.

[0159] The term "titration dose" refers to the amount of dual agonist administered to the patient in each dose during the titration period, prior to the administration of the therapeutic dose. Each titration dose is between 0.1 mg and 10.0 mg of dual agonist. The doses, dosing regimens, and administration protocols presented herein are equivalent to the titration dose.

[0160] The term "treatment dose" refers to the amount of dual agonist administered to the patient in each dose during the treatment period. Each treatment dose is between 0.1 mg and 10.0 mg of dual agonist. The doses, drug regimens, and administration protocols presented herein are equivalent to the treatment dose.

[0161] f. Medication regimen According to the present invention, a dual GLP-1 / GLP-2 agonist is for use in a method to reduce or prevent weight gain, reduce food intake, reduce appetite, promote weight loss, or treat obesity, morbid obesity, obesity-related gallbladder disease, or obesity-induced sleep apnea, the method comprising the step of administering a dual agonist to a patient in a dose of approximately 0.1 mg to 10.0 mg. In other words, the method comprises the step of administering a dual agonist to a patient in an amount of approximately 0.1 mg to 10.0 mg.

[0162] A dose of approximately 0.1 mg to 10.0 mg of the dual agonist is administered to the patient as a single dose (i.e., a single-dose event). In other words, the dual agonist is administered to the patient in a single-dose formulation of approximately 0.1 mg to approximately 10.0 mg. This single-dose formulation may be administered to the patient once or multiple times, and each of the multiple formulations for administration to the patient does not need to contain the same amount of dual agonist. In other words, the dual agonist may be administered to the patient in a series of single doses, and each single dose may not contain the same amount of dual agonist. Each administration of the dual agonist to the patient can be independently selected to be a dose of approximately 0.1 mg to approximately 10.0 mg.

[0163] Accordingly, the present invention provides a GLP-1 / GLP-2 dual agonist as described herein, or a pharmaceutically acceptable salt or solvate thereof, for use in a method of reducing or preventing weight gain, reducing food intake, reducing appetite, promoting weight loss, or treating obesity, morbid obesity, obesity-related gallbladder disease, or obesity-induced sleep apnea, the method comprising at least one administration of the dual agonist to a patient in a dose of about 0.1 mg to 10.0 mg.

[0164] a.Dose In one embodiment, the dual agonist is administered to the patient in a dose of approximately 0.1 mg to approximately 10.0 mg. In another embodiment, the dual agonist is administered to the patient in a dose of approximately 1.0 mg to approximately 10.0 mg. In another embodiment, the dual agonist is administered to the patient in a dose of approximately 1.1 mg to approximately 10.0 mg, approximately 1.2 mg to approximately 10.0 mg, approximately 1.3 mg to approximately 10.0 mg, or approximately 1.4 mg to approximately 10.0 mg. In another embodiment, the dual agonist is administered to the patient in a dose of approximately 1.5 mg to approximately 10.0 mg. In another embodiment, the dual agonist is administered to the patient in a dose of approximately 1.6 mg to approximately 10.0 mg, approximately 1.7 mg to approximately 10.0 mg, approximately 1.8 mg to approximately 10.0 mg, or approximately 1.9 mg to approximately 10.0 mg. In one embodiment, the dual agonist is administered to the patient in a dose of approximately 2.0 mg to approximately 10.0 mg. In another embodiment, the dual agonist is administered to the patient in a dose of approximately 2.1 mg to approximately 10.0 mg, or approximately 2.2 mg to approximately 10.0 mg. In another embodiment, the dual agonist is administered to the patient in a dose of approximately 2.25 mg to approximately 10.0 mg. In another embodiment, the dual agonist is administered to the patient in a dose of approximately 3.0 mg to approximately 10.0 mg, approximately 4.0 mg to approximately 10.0 mg, approximately 5.0 mg to approximately 10.0 mg, approximately 6.0 mg to approximately 10.0 mg, approximately 7.0 mg to approximately 10.0 mg, approximately 8.0 mg to approximately 10.0 mg, or approximately 9.0 mg to approximately 10.0 mg.

[0165] In one embodiment, the dual agonist is administered to the patient in a dose of approximately 0.1 mg to approximately 9.0 mg. In one embodiment, the dual agonist is administered to the patient in a dose of approximately 1.0 mg to approximately 9.0 mg. In one embodiment, the dual agonist is administered to the patient in a dose of approximately 1.1 mg to approximately 9.0 mg, approximately 1.2 mg to approximately 9.0 mg, approximately 1.3 mg to approximately 9.0 mg, or approximately 1.4 mg to approximately 9.0 mg. In one embodiment, the dual agonist is administered to the patient in a dose of approximately 1.5 mg to approximately 9.0 mg. In one embodiment, the dual agonist is administered to the patient in a dose of approximately 1.6 mg to approximately 9.0 mg, approximately 1.7 mg to approximately 9.0 mg, approximately 1.8 mg to approximately 9.0 mg, or approximately 1.9 mg to approximately 9.0 mg. In one embodiment, the dual agonist is administered to the patient in a dose of approximately 2.0 mg to approximately 9.0 mg. In another embodiment, the dual agonist is administered to the patient in a dose of approximately 2.1 mg to approximately 9.0 mg, or approximately 2.2 mg to approximately 9.0 mg. In another embodiment, the dual agonist is administered to the patient in a dose of approximately 2.25 mg to approximately 9.0 mg. In another embodiment, the dual agonist is administered to the patient in a dose of approximately 3.0 mg to approximately 9.0 mg, approximately 4.0 mg to approximately 9.0 mg, approximately 5.0 mg to approximately 9.0 mg, approximately 6.0 mg to approximately 9.0 mg, approximately 7.0 mg to approximately 9.0 mg, or approximately 8.0 mg to approximately 9.0 mg.

[0166] In one embodiment, the dual agonist is administered to the patient in a dose of approximately 0.1 mg to approximately 8.0 mg. In another embodiment, the dual agonist is administered to the patient in a dose of approximately 1.0 mg to approximately 8.0 mg. In another embodiment, the dual agonist is administered to the patient in a dose of approximately 1.1 mg to approximately 8.0 mg, approximately 1.2 mg to approximately 8.0 mg, approximately 1.3 mg to approximately 8.0 mg, or approximately 1.4 mg to approximately 8.0 mg. In another embodiment, the dual agonist is administered to the patient in a dose of approximately 1.5 mg to approximately 8.0 mg. In another embodiment, the dual agonist is administered to the patient in a dose of approximately 1.6 mg to approximately 8.0 mg, approximately 1.7 mg to approximately 8.0 mg, approximately 1.8 mg to approximately 8.0 mg, or approximately 1.9 mg to approximately 8.0 mg. In one embodiment, the dual agonist is administered to the patient in a dose of approximately 2.0 mg to approximately 8.0 mg. In another embodiment, the dual agonist is administered to the patient in a dose of approximately 2.1 mg to approximately 8.0 mg, or approximately 2.2 mg to approximately 8.0 mg. In another embodiment, the dual agonist is administered to the patient in a dose of approximately 2.25 mg to approximately 8.0 mg. In another embodiment, the dual agonist is administered to the patient in a dose of approximately 3.0 mg to approximately 8.0 mg, approximately 4.0 mg to approximately 8.0 mg, approximately 5.0 mg to approximately 8.0 mg, approximately 6.0 mg to approximately 8.0 mg, or approximately 7.0 mg to approximately 8.0 mg.

[0167] In one embodiment, the dual agonist is administered to the patient in doses of approximately 1.0 mg to approximately 7.5 mg, approximately 1.0 mg to approximately 7.0 mg, approximately 1.0 mg to approximately 6.0 mg, approximately 1.0 mg to approximately 5.0 mg, approximately 1.0 mg to approximately 4.0 mg, or approximately 1.0 mg to approximately 3.5 mg. In one embodiment, the dual agonist is administered to the patient in doses of approximately 1.5 mg to approximately 7.5 mg. In one embodiment, the dual agonist is administered to the patient in doses of approximately 1.5 mg to approximately 7.0 mg, approximately 1.5 mg to approximately 6.0 mg, approximately 1.5 mg to approximately 5.0 mg, approximately 1.5 mg to approximately 4.0 mg, or approximately 1.5 mg to approximately 3.5 mg. In one embodiment, the dual agonist is administered to the patient in doses of approximately 2.0 mg to 7.5 mg, 2.0 mg to 7.0 mg, 2.0 mg to 6.0 mg, 2.0 mg to 5.0 mg, 2.0 mg to 4.0 mg, or 2.0 mg to 3.5 mg. In another embodiment, the dual agonist is administered to the patient in doses of approximately 2.25 mg to 7.5 mg, 2.25 mg to 7.0 mg, 2.25 mg to 6.0 mg, 2.25 mg to 5.0 mg, 2.25 mg to 4.0 mg, or 2.25 mg to 3.5 mg. In yet another embodiment, the dual agonist is administered to the patient in doses of approximately 4.0 mg to 7.5 mg. In one embodiment, the dual agonist is administered to the patient in a dose of approximately 4.0 mg to approximately 6.0 mg.

[0168] In one embodiment, the dual agonist is administered to the patient in doses of 1.0 mg to 7.5 mg, 1.0 mg to 7.0 mg, 1.0 mg to 6.0 mg, 1.0 mg to 5.0 mg, 1.0 mg to 4.0 mg, or 1.0 mg to 3.5 mg. In one embodiment, the dual agonist is administered to the patient in doses of 1.5 mg to 7.5 mg. In one embodiment, the dual agonist is administered to the patient in doses of 1.5 mg to 7.0 mg, 1.5 mg to 6.0 mg, 1.5 mg to 5.0 mg, 1.5 mg to 4.0 mg, or 1.5 mg to 3.5 mg. In one embodiment, the dual agonist is administered to the patient in doses of 2.0 mg to 7.5 mg, 2.0 mg to 7.0 mg, 2.0 mg to 6.0 mg, 2.0 mg to 5.0 mg, 2.0 mg to 4.0 mg, or 2.0 mg to 3.5 mg. In one embodiment, the dual agonist is administered to the patient in doses of 2.25 mg to 7.5 mg, 2.25 mg to 7.0 mg, 2.25 mg to 6.0 mg, 2.25 mg to 5.0 mg, 2.25 mg to 4.0 mg, or 2.25 mg to 3.5 mg. In one embodiment, the dual agonist is administered to the patient in doses of 4.0 mg to 7.5 mg. In one embodiment, the dual agonist is administered to the patient in doses of 4.0 mg to 6.0 mg.

[0169] In one embodiment, the dose is greater than 0.6 mg. In another embodiment, the dual agonist is administered to the patient at a dose of approximately 1.5 mg.

[0170] In some embodiments, the dual agonist is administered to the patient in doses of approximately 1.0 mg, 1.5 mg, 2.0 mg, 2.25 mg, 2.5 mg, 3.0 mg, 3.5 mg, 4.0 mg, 4.5 mg, 5.0 mg, 5.5 mg, 6.0 mg, 6.5 mg, 7.0 mg, 7.5 mg, 8.0 mg, 9.0 mg, or 10.0 mg. In some embodiments, the dual agonist is administered to the patient in doses of 1.0 mg, 1.5 mg, 2.0 mg, 2.25 mg, 2.5 mg, 3.0 mg, 3.5 mg, 4.0 mg, 4.5 mg, 5.0 mg, 5.5 mg, 6.0 mg, 6.5 mg, 7.0 mg, 7.5 mg, 8.0 mg, 9.0 mg, or 10.0 mg.

[0171] b. Administration The administration of the dual agonists described herein may be by any common or standard mode of administration in the art, for example, by oral, intravenous, intramuscular, subcutaneous, sublingual, intranasal, intradermal, suppository, or implantation route. In the preferred embodiments of the present invention described herein, administration is by subcutaneous injection.

[0172] The drug regimen of the present invention may include administering one or more doses of a dual agonist. Accordingly, in some embodiments, the present invention provides a GLP-1 / GLP-2 dual agonist as described herein, or a pharmaceutically acceptable salt or solvate thereof, for use in a method of reducing or preventing weight gain, reducing food intake, reducing appetite, promoting weight loss, or treating obesity, morbid obesity, obesity-related gallbladder disease, or obesity-induced sleep apnea, the method comprising one or more administrations of the dual agonist to a patient in doses of about 0.1 mg to 10.0 mg. In some embodiments, the method comprises two or three or more administrations of the dual agonist to a patient in doses of about 0.1 mg to 10.0 mg. In some embodiments, each administration of the dual agonist to a patient is in doses of about 0.1 mg to 10.0 mg.

[0173] In some aspects of the present invention, where the method involves multiple administrations of a dual agonist to a patient, the dose of the dual agonist may differ in each administration. In other words, it is not necessary for the dose of the dual agonist to be the same in each administration. However, in other aspects of the present invention, where the method involves multiple administrations of a dual agonist to a patient, the dose of the dual agonist may be the same or substantially the same in each administration.

[0174] In some embodiments of the present invention, a series of single doses are delivered to a patient, and in the initial course of single doses, the dose of the dual agonist in the single-dose formulation may be subsequently increased. In some embodiments, the initial course may consist of 2, 3, 4, 5, 6, 7, 8, 9, 10, or 11 or more doses in which the amount of the dual agonist in the single-dose formulation increases. In some embodiments, after the initial course, the subsequent dose of the dual agonist in the single-dose formulation may be the same as, or less than, the final dose of the initial course, or more than the final dose of the initial course. In certain embodiments, after the initial course, the subsequent dose of the dual agonist in the single-dose formulation may be the same as or approximately the same as the final dose of the initial course.

[0175] In a preferred embodiment, the administration includes weekly administration of a dual agonist.

[0176] The reference to “weekly” is intended to mean approximately every 7 days, for example, approximately every 5, 5.5, 6, 6.5, 7, 7.5, 8, 8.5, or 9 days, where each “day” is counted as a period of approximately 24 hours. As understood in this field, the time between doses may vary to some extent so that each dose is not separated exactly at the same time. This is often directed at the discretion of the physician. Therefore, doses may be spaced out over time by a range of clinically acceptable intervals.

[0177] In one aspect of the present invention as described herein, the reference to “weekly” may mean 7 days ± 2 days. In other words, administration may be given up to 2 days before the day described, including 2 days before, or up to 2 days after, including 2 days after. Therefore, administration may be given 2 or 1 day before, or 1 or 2 days after, the day described.

[0178] In one embodiment, the dual agonist is administered weekly in doses of approximately 1.5 mg to 7.5 mg, for example, approximately 1.5 mg to 6.0 mg, for example, approximately 1.5 mg to 4.0 mg, for example, approximately 1.5 mg to 3.5 mg. In another embodiment, the dual agonist is administered weekly in doses of approximately 2.0 mg to 7.5 mg, for example, approximately 2.0 mg to 6.0 mg, for example, approximately 2.0 mg to 4.0 mg, for example, approximately 2.0 mg to 3.5 mg. In yet another embodiment, the dual agonist is administered weekly in doses of approximately 2.25 mg to 3.5 mg.

[0179] In one embodiment, the dual agonist is administered weekly in doses of 1.5 mg to 7.5 mg, for example, 1.5 mg to 6.0 mg, for example, 1.5 mg to 4.0 mg, for example, 1.5 mg to 3.5 mg. In another embodiment, the dual agonist is administered weekly in doses of 2.0 mg to 7.5 mg, for example, 2.0 mg to 6.0 mg, for example, 2.0 mg to 4.0 mg, for example, 2.0 mg to 3.5 mg. In yet another embodiment, the dual agonist is administered weekly in doses of 2.25 mg to 3.5 mg.

[0180] In one embodiment, the number of doses administered to the patient may be 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12, or 13 or more doses. In other words, in some embodiments, the dual agonist is administered to the patient 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12, or 13 or more times. In some embodiments, the method includes 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12, or 13 or more doses of the dual agonist. In some embodiments, the dual agonist is administered to the patient in doses of approximately 0.1 to 10.0 mg (or any other dose as described herein) 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12, or 13 or more times. In some embodiments, the method involves administering a dual agonist in doses of approximately 0.1 to 10.0 mg (or any other dose described herein) one, two, three, four, five, six, seven, eight, nine, ten, eleven, or twelve, or thirteen or more doses. In one embodiment, four doses are administered to the patient. In one embodiment, the method involves administering a dual agonist in doses of approximately 0.1 to 10.0 mg (or any other dose described herein) four times. In one embodiment, twelve doses are administered to the patient. In one embodiment, the method involves administering a dual agonist in doses of approximately 0.1 to 10.0 mg (or any other dose described herein) twelve times.

[0181] In one embodiment, the agonist may be administered in the same dose each time. In one embodiment, each administration of the dual agonist to the patient is in a dose of approximately 0.1 mg to 10.0 mg.

[0182] In one embodiment, several doses are administered to the patient over a period of several weeks or several months, or for a year or longer.

[0183] In one embodiment, several doses are administered to the patient weekly and over a period of several weeks or months, or for a year or longer.

[0184] In one embodiment, the agonist may be administered in gradually increasing doses.

[0185] c. Titration and treatment In some embodiments, the dual agonist is administered to the patient according to a titration regimen. The titration regimen includes an initial set of one or more doses of the dual agonist during the "titration period," followed by a set of one or more doses of the dual agonist during the "treatment period." Typically, the dose of the dual agonist in each dose during the titration period is lower than the dose in each dose during the treatment period.

[0186] The primary objective of the titration period is to allow the patient to become accustomed to the side effects of the dual agonist. Initial doses of the dual agonist may cause side effects, but as the patient adapts, the severity decreases with further doses. Administering low doses of the dual agonist during the titration period can reduce the initial severity of these side effects. A secondary objective of the titration period may be to determine the appropriate dose of the dual agonist for the patient. The dose of the dual agonist may be increased over the titration period, allowing the physician to observe side effects at various doses and thereby determine the appropriate dose for treatment.

[0187] Accordingly, in some embodiments, the present invention provides a GLP-1 / GLP-2 dual agonist as described herein, or a pharmaceutically acceptable salt or solvate thereof, for use in a method of reducing or preventing weight gain, reducing food intake, reducing appetite, promoting weight loss, or treating obesity, morbid obesity, obesity-related gallbladder disease, or obesity-induced sleep apnea, the method comprising at least one administration of the dual agonist to a patient in a dose of about 0.1 mg to 10.0 mg, at least one administration of the dual agonist to a patient in a titratable dose, and at least one administration of the dual agonist to a patient in a therapeutic dose. In other words, in some embodiments, the method comprises administering the dual agonist to a patient at least once in a titratable dose and at least once in a therapeutic dose.

[0188] In some embodiments, the method includes multiple administrations (i.e., two or three or more administrations) of the dual agonist to the patient in titration doses. In some embodiments, the method includes three or four or more, four or five or more, or five or six or more administrations of the dual agonist to the patient in titration doses. In some embodiments, the method includes one, two, three, four, or five administrations of the dual agonist to the patient in titration doses. In preferred embodiments, the method includes two administrations of the dual agonist to the patient in titration doses. In preferred embodiments, the method includes five administrations of the dual agonist to the patient in titration doses.

[0189] In one embodiment, there may be at least one initial titration period of low doses before increasing the dose. In one embodiment, the titration period may consist of one, two, three, or four low doses, preferably the same dose in each instance. In one embodiment, the titration period consists of one low dose. In one embodiment, the titration period consists of two low doses.

[0190] In a preferred embodiment, the titration dose is administered weekly. In other words, in some embodiments, the method involves administering a dual agonist to the patient once a week in a titration dose.

[0191] The titration dose may be any dose of the dual agonist as described elsewhere in this specification. In some embodiments, the titration dose is about 0.1 mg to about 10.0 mg. In some embodiments, the titration dose is about 1.0 mg to about 6.0 mg, for example, about 1.5 mg to about 6.0 mg. Thus, in some embodiments, the method includes at least one administration of the dual agonist to the patient at a titration dose of about 1.5 mg to about 6.0 mg. In one embodiment, the titration dose is about 1.0 mg to about 4.0 mg, for example, about 1.5 mg to about 4.0 mg. In one embodiment, the titration dose is about 1.0 mg to about 3.5 mg, for example, about 1.5 mg to about 3.5 mg, or about 1.5 mg to about 3.0 mg. In one embodiment, the titration dose is 1.0 mg, 2.0 mg, 2.25 mg, 3.0 mg, 3.5 mg, 4.0 mg, 4.5 mg, 5.0 mg, 5.5 mg, or 6.0 mg, or an approximate amount thereof. In some embodiments, the titration dose is 2.0 mg. In some embodiments, the titration dose is 2.0 mg administered once a week. In some embodiments, the titration dose is 4.0 mg. In some embodiments, the titration dose is 4.0 mg administered once a week.

[0192] The titration dose does not need to be the same for each administration. In other words, different titration doses may be administered to the patient within the titration period. Accordingly, in some embodiments, the present invention provides a GLP-1 / GLP-2 dual agonist as described herein, or a pharmaceutically acceptable salt or solvate thereof, for use in a method of reducing or preventing weight gain, reducing food intake, reducing appetite, promoting weight loss, or treating obesity, morbid obesity, obesity-related gallbladder disease, or obesity-induced sleep apnea, the method comprising at least one administration of the dual agonist to the patient at a dose of about 0.1 mg to 10.0 mg, at least one administration of the dual agonist to the patient at one or more titration doses, and at least one administration of the dual agonist to the patient at a therapeutic dose.

[0193] In some embodiments, the method comprises two or three or more, three or four or more, or four or five or more different titrating doses. In some embodiments, the method comprises two, three, or four different titrating doses. In preferred embodiments, the method comprises two different titrating doses. Each titrating dose may be one of the doses of the dual agonist described elsewhere in this specification.

[0194] In some embodiments, all titration doses are the same (i.e., there is one titration dose that is the same for all administrations of the dual agonist to the patient during the titration period).

[0195] In some embodiments, the method includes a single administration of a dual agonist to a patient at a titrating dose of 3.5 mg. In some embodiments, the method includes two administrations of a dual agonist to a patient at a titrating dose of 2.0 mg. In some embodiments, the method includes two administrations of a dual agonist to a patient at a titrating dose of 2.0 mg, and three administrations of a dual agonist to a patient at a titrating dose of 4.0 mg.

[0196] In some embodiments, the method includes multiple administrations (i.e., two or three or more administrations) of a dual agonist at a therapeutic dose to the patient. In some embodiments, the method includes three or four or more, four or five or more, five or six or more, six or seven or more, seven or eight or more, eight or nine or more, nine or ten or more, ten or eleven or more, eleven or twelve or thirteen or more, or twelve or thirteen or more administrations of a dual agonist at a therapeutic dose to the patient. In some embodiments, the method includes one, two, three, four, five, six, seven, eight, nine, ten, eleven, or twelve administrations of a dual agonist at a therapeutic dose to the patient. In preferred embodiments, the method includes three administrations of a dual agonist at a therapeutic dose to the patient. In preferred embodiments, the method includes ten administrations of a dual agonist at a therapeutic dose to the patient. In preferred embodiments, the method includes seven administrations of a dual agonist at a therapeutic dose to the patient.

[0197] Therapeutic doses may be administered for as long as necessary. A therapeutic dose of dual agonist may be administered to a patient for a period of time ranging from, for example, one month to 20 years, such as one month, two months, three months, four months, five months, six months, seven months, eight months, nine months, ten months, eleven months, one year, two years, three years, four years, five years, six years, seven years, eight years, nine years, ten years, eleven years, twelve years, thirteen years, fourteen years, fifteen years, sixteen years, seventeen years, eighteen years, nineteen years, or twenty years.

[0198] For example, the therapeutic dose may be administered to a patient weekly, for example, over a period of 1 month to 20 years, for example, 1 month, 2 months, 3 months, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, 1 year, 2 years, 3 years, 4 years, 5 years, 6 years, 7 years, 8 years, 9 years, 10 years, 11 years, 12 years, 13 years, 14 years, 15 years, 16 years, 17 years, 18 years, 19 years, or 20 years.

[0199] The therapeutic dose may be any dose of the dual agonist described herein. In some embodiments, the therapeutic dose is approximately 0.1 mg to approximately 10.0 mg. In some embodiments, the therapeutic dose is approximately 1.0 mg to approximately 10.0 mg, approximately 1.5 mg to approximately 10.0 mg, approximately 2.0 mg to approximately 10.0 mg, approximately 2.25 mg to approximately 10.0 mg, approximately 3.0 mg to approximately 10.0 mg, approximately 4.0 mg to approximately 10.0 mg, approximately 5.0 mg to approximately 10.0 mg, approximately 6.0 mg to approximately 10.0 mg, approximately 7.0 mg to approximately 10.0 mg, approximately 8.0 mg to approximately 10.0 mg, or approximately 9.0 mg to approximately 10.0 mg. In some embodiments, the therapeutic dose is approximately 1.0 mg, 1.5 mg, 2.0 mg, 2.25 mg, 2.5 mg, 3.0 mg, 3.5 mg, 4.0 mg, 4.5 mg, 5.0 mg, 5.5 mg, 6.0 mg, 6.5 mg, 7.0 mg, 7.5 mg, 8.0 mg, 9.0 mg, or 10.0 mg. In some embodiments, the therapeutic dose is 1.0 mg, 1.5 mg, 2.0 mg, 2.25 mg, 2.5 mg, 3.0 mg, 3.5 mg, 4.0 mg, 4.5 mg, 5.0 mg, 5.5 mg, 6.0 mg, 6.5 mg, 7.0 mg, 7.5 mg, 8.0 mg, 9.0 mg, or 10.0 mg.

[0200] Typically, in embodiments where a dual agonist is administered to a patient multiple times at therapeutic doses (i.e., multiple administrations of a dual agonist at therapeutic doses), all administrations during the treatment period are the same dose. Therefore, in some embodiments, all therapeutic doses are the same (i.e., there is one therapeutic dose that is the same for all administrations of the dual agonist to the patient during the treatment period).

[0201] However, the therapeutic dose does not need to be the same for each administration. In other words, different therapeutic doses may be administered to the patient during the treatment period. The therapeutic dose may be varied according to the patient's response to the dual agonist. For example, if a patient experiences a serious side effect at a given therapeutic dose, the therapeutic dose may be reduced in subsequent administrations to lessen the severity of the side effect.

[0202] Accordingly, in some embodiments, the present invention provides GLP-1 / GLP-2 dual agonists as described herein, or pharmaceutically acceptable salts or solvates thereof, for use in methods for reducing or preventing weight gain, reducing food intake, reducing appetite, promoting weight loss, or treating obesity, morbid obesity, obesity-related gallbladder disease, or obesity-induced sleep apnea, the methods comprising at least one administration of the dual agonist to a patient in a dose of about 0.1 mg to 10.0 mg, at least one administration of the dual agonist to a patient in one or more titration doses, and at least one administration of the dual agonist to a patient in one or more therapeutic doses.

[0203] In some embodiments, the method includes two or three or more, three or four or more, or four or five or more different therapeutic doses. In some embodiments, the method includes two, three, or four different therapeutic doses. Each therapeutic dose may be one of the doses of the dual agonist described elsewhere in this specification.

[0204] Typically, the therapeutic dose is higher than the titration dose. Therefore, in some embodiments, the therapeutic dose is higher than the titration dose. In some embodiments, the therapeutic dose is higher than some or all of the titration dose.

[0205] However, the therapeutic dose may be lower than the titration dose. This may be the case, for example, when the titration dose is increased as the titration period progresses (i.e., the titration dose increases over sequential administration), but then the dose is reduced for therapeutic purposes to account for the side effects the patient experiences as the titration dose increases. Thus, in some embodiments, the therapeutic dose is lower than the titration dose. In some embodiments, the therapeutic dose is lower than some or all of the titration dose.

[0206] As described herein, one purpose of titration is to identify an appropriate therapeutic dose. Therefore, in some embodiments, the therapeutic dose is determined by a physician observing the effect of the titration on the patient. In other words, the therapeutic dose may depend on the titration.

[0207] In a preferred embodiment, the therapeutic dose is administered weekly. In other words, in some embodiments, the method includes administering a dual agonist to a patient once a week at a therapeutic dose. In some embodiments, the method includes administering a dual agonist to a patient once a week at a titrating dose and once a week at a therapeutic dose. In other words, once a week administration of a therapeutic dose of a dual agonist is a continuation of once a week administration at a titrating dose.

[0208] In one embodiment, the titration period may be followed by one or more doses higher than the titrated dose. In one embodiment, the titration period may be followed by one, two, three, or four doses higher than the titrated dose. In one embodiment, the titration period may be followed by three doses higher than the titrated dose. In one embodiment, the titration period may be followed by ten doses higher than the titrated dose. In one embodiment, the titration period may be followed by seven doses higher than the titrated dose. In one embodiment, the titration period consists of one dose, followed by three doses higher than the titrated dose. In one embodiment, the titration period consists of two doses, followed by ten doses higher than the titrated dose. In one embodiment, the high dose is between approximately 3 mg and approximately 8 mg. In one embodiment, the high dose is between approximately 3 mg and approximately 8 mg.

[0209] In some embodiments, the method comprises a single administration of a dual agonist to the patient at a titration dose of 3.5 mg, and three administrations of a dual agonist to the patient at a therapeutic dose of 6.0 mg, each administration being once a week.

[0210] In some embodiments, the method comprises two administrations of a dual agonist to the patient at a titration dose of 2.0 mg, and ten administrations of a dual agonist to the patient at a therapeutic dose of 4.0 mg, with each administration occurring once a week.

[0211] In some embodiments, the method includes two administrations of a dual agonist to the patient at a titration dose of 2.0 mg, three administrations of a dual agonist to the patient at a titration dose of 4.0 mg, and seven administrations of a dual agonist to the patient at a therapeutic dose of 6.0 mg, each administration being once a week.

[0212] In one embodiment, the higher dose (after the drop interval) is 6.0 mg, 7.0 mg, 7.5 mg, or 8.0 mg, preferably 6.0 mg, or an approximate number thereof.

[0213] In a preferred embodiment, the titration dose is administered weekly.

[0214] In a preferred embodiment, the titrated dose is administered weekly.

[0215] Advantageously, subjects may not experience nausea or vomiting (or other adverse gastrointestinal effects) during the titration period. This allows for a shorter or faster titration period prior to administering higher doses.

[0216] In one embodiment, multiple titration periods may exist.

[0217] In one aspect of the present invention, a further dose may be administered after the above-described dose; that is, the subject may be administered a dose following the initial dose described herein.

[0218] Additional medication may be administered once a week.

[0219] Dual agonist administration can be continued for as long as necessary.

[0220] The additional doses mentioned above may be administered as needed over a period of time ranging from, for example, one month to 20 years, such as one month, two months, three months, four months, five months, six months, seven months, eight months, nine months, ten months, eleven months, one year, two years, three years, four years, five years, six years, seven years, eight years, nine years, ten years, eleven years, twelve years, thirteen years, fourteen years, fifteen years, sixteen years, seventeen years, eighteen years, nineteen years, or twenty years.

[0221] g. Clinical outcomes In a preferred embodiment, the patient does not experience nausea and / or vomiting as a side effect after administration of the dual agonist.

[0222] In a preferred embodiment, the patient has a decreased appetite. In a preferred embodiment, the patient has a decreased appetite after administration of a dual agonist.

[0223] The term "appetite" refers to a patient's desire to consume food. A patient's appetite can be determined by measuring how much food the patient consumes using techniques known in the art and described herein, such as the mixed-food test or standard-food test described in Example 6 herein. Thus, in some embodiments, appetite is measured using a mixed-food test. In some embodiments, appetite is measured using a standard-food test. In some embodiments, after administration of a dual agonist, the patient's appetite decreases by at least 5%. In some embodiments, after administration of a dual agonist, the patient's appetite decreases by at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 55%, or at least 60%.

[0224] In a preferred embodiment, the patient's food intake decreases after administration of a dual agonist. “Food consumption” is synonymous with “food intake.” Therefore, in a preferred embodiment, the patient's food intake decreases after administration of a dual agonist. The term “food consumption” refers to the amount of food a patient consumes in a given setting or period, for example, in one meal, over multiple meals, or over a specific period. The patient’s food consumption can be measured by techniques known in the art and described herein, such as the mixed-food test or standard-food test described in Example 6 herein. Therefore, in some embodiments, food consumption is measured using a mixed-food test. In some embodiments, food consumption is measured using a standard-food test. In some embodiments, the patient’s food consumption decreases by at least 5% after administration of a dual agonist. In some embodiments, after administration of a dual agonist, the patient's food intake decreases by at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 55%, or at least 60%. In some embodiments, after administration of a dual agonist, the amount of food consumed by the patient decreases to 95% or less of the amount of food consumed by the patient before administration of the dual agonist. In some embodiments, after administration of a dual agonist, the amount of food consumed by the patient decreases to 90% or less, 85% or less, 80% or less, 75% or less, 70% or less, 65% or less, 60% or less, 55% or less, 50% or less, 45% or less, or 40% or less of the amount of food consumed by the patient before administration of the dual agonist. In a preferred embodiment, after administration of the dual agonist, the amount of food consumed by the patient is reduced to 65% or less of the amount of food consumed by the patient before administration of the dual agonist.

[0225] In some embodiments, the patient loses weight after administration of a dual agonist. In some embodiments, after administration of a dual agonist, the patient's weight decreases by at least 5%, at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 55%, or at least 60%.

[0226] In some embodiments, the patient's body mass index (BMI) decreases after administration of a dual agonist. In some embodiments, after administration of a dual agonist, the patient's BMI decreases by at least 5%, at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 55%, or at least 60%. The patient's BMI may be determined by methods known in the art.

[0227] h.Tonicity agent In one embodiment, the composition or pharmaceutical composition may be an isotonic parenteral composition.

[0228] In one embodiment, the composition or pharmaceutical composition includes an isotonic agent, for example, one described in WO2020 / 249778. The isotonic parenteral pharmaceutical composition includes a GLP-1 / GLP-2 dual agonist as described herein, a. A phosphate buffering agent component in a concentration of approximately 5 mM to approximately 50 mM, preferably approximately 10 mM to approximately 40 mM, more preferably approximately 15 mM to approximately 30 mM, and most preferably approximately 20 mM. b. One or more isotonic agents in a concentration of approximately 190 mM to 240 mM It may include, The one or more isotonic agents include a nonionic isotonic agent, or a nonionic isotonic agent, preferably a nonionic isotonic agent, and the nonionic isotonic agent is mannitol. The composition further comprises a solvent, The above composition has a pH of approximately 6.0 to 8.2, preferably 7.0 to 8.0. The mannitol is preferably D-mannitol.

[0229] In one embodiment, the GLP-1 / GLP-2 dual agonist has the following sequence: It comprises H[Aib]EGSFTSELATILD[Ψ]QAARDFIAWLIQHKITD (SEQ ID NO: 34), more preferably, a. Hy-H[Aib]EGSFTSELATILD[K([17-carboxy-heptadecanoyl]-isoGlu)]QAARDFIAWLIQHKITD-OH(CPD1OH), or b.Hy-H[Aib]EGSFTSELATILD[K([17-carboxy-heptadecanoyl]-isoGlu)]QAARDFIAWLIQHKITD-NH2(CPD1NH2) Includes.

[0230] In a preferred embodiment, the double agonist is Hy-H[Aib]EGSFTSELATILD[K([17-carboxy-heptadecanoyl]-isoGlu)]QAARDFIAWLIQHKITD-OH (compound 18).

[0231] Alternatively, the double agonist is Hy-H[Aib]EGTFTSELATILD[K([17-carboxy-heptadecanoyl]-isoGlu)]QAARDFIAWLIQHKITD-OH (compound 19).

[0232] In one embodiment, compounds such as compound 18 may be formulated as follows. [Table 1]

[0233] i. Medical condition The dual agonists described herein possess the biological activity of both GLP-1 and GLP-2.

[0234] GLP-2 induces significant proliferation of the small intestinal mucosal epithelium by stimulating stem cell proliferation in crypts and suppressing apoptosis on villus (Drucker et al. Proc Natl Acad Sci US A. 1996, 93:7911-6). GLP-2 also has a proliferative effect on the colon. GLP-2 also suppresses gastric emptying and gastric acid secretion (Wojdemann et al. J Clin Endocrinol Metab. 1999, 84:2513-7), enhances the intestinal barrier function (Benjamin et al. Gut. 2000, 47:112-9), stimulates intestinal hexose transport through upregulation of glucose transporters (Cheeseman, Am J Physiol. 1997, R1965-71), and increases intestinal blood flow (Guan et al. Gastroenterology. 2003, 125, 136-47).

[0235] The beneficial effects of GLP-2 in the small intestine have generated considerable interest in its use in the treatment of intestinal diseases or injuries (Sinclair and Drucker, Physiology 2005: 357-65). Furthermore, GLP-2 has been shown to prevent or reduce mucosal epithelial damage in a wide range of preclinical models of intestinal injury, including chemotherapy-induced colitis, ischemia-reperfusion injury, dextran sulfate-induced colitis, and hereditary models of inflammatory bowel disease (Sinclair and Drucker Physiology 2005: 357-65). The GLP-2 analog teduglutide (Gly2-hGLP-2) is approved for the treatment of short bowel syndrome under the trade names Gattex and Revestive.

[0236] GLP-1 is a peptide hormone known for its important role in glucose homeostasis. When secreted from the gastrointestinal tract in response to nutrient intake, GLP-1 enhances glucose-stimulated insulin secretion from β-cells (Kim and Egan, 2008, Pharmacol. Rev. 470-512). Furthermore, GLP-1 or its analogs have been shown to increase somatostatin secretion and suppress glucagon secretion (Holst JJ, 2007, Physiol Rev. 1409-1439).

[0237] Beyond its primary effect on glucose-stimulated insulin secretion, GLP-1 is also known as a major regulator of appetite, food intake, and body weight. Furthermore, GLP-1 can suppress gastric emptying and gastrointestinal motility in both rodents and humans, possibly through GLP-1 receptors present in the gastrointestinal tract (Holst JJ, 2007, Physiol Rev. 1409-1439, Hellstrom et al., 2008, Neurogastroenterol Motil. Jun; 20(6):649-659). In addition, GLP-1 is thought to participate in glucose homeostasis and lipid metabolism in tissues such as muscle, liver, and adipose tissue, and to have insulin-like effects in major extrasplenic tissues (Kim and Egan, 2008, Pharmacol. Rev. 470-512).

[0238] The dual agonist compounds described herein are found to be used, among other things, to reduce or inhibit weight gain, slow gastric emptying or intestinal transit, reduce food intake, reduce appetite, or promote weight loss. The effect on body weight may be mediated, partially or completely, through a reduction in food intake, appetite, or intestinal transit.

[0239] Therefore, dual agonists can be used for the prevention or treatment of obesity, morbid obesity, obesity-related gallbladder disease, or obesity-induced sleep apnea.

[0240] As described above, surprisingly, it was found that a particular drug regimen according to the present invention was effective in reducing appetite in patients without also causing the expected side effects of nausea and vomiting.

[0241] The effects on weight may be therapeutic or cosmetic.

[0242] In a further embodiment, a therapeutic kit is provided comprising a dual agonist according to the present invention, or a pharmaceutically acceptable salt or solvate thereof, for use in a method of reducing or preventing weight gain, reducing food intake, reducing appetite, promoting weight loss, or treating obesity, morbid obesity, obesity-related gallbladder disease, or obesity-induced sleep apnea, the method comprising the step of administering the dual agonist to a patient in a dose of about 0.1 mg to about 8.0 mg.

[0243] The following embodiments are provided to illustrate preferred embodiments of the present invention and are not intended to limit the scope of the invention in any way. [Examples]

[0244] The following embodiments are provided to illustrate preferred embodiments of the present invention and are not intended to limit the scope of the invention.

[0245] j. Materials and Methods The GLP-1 / GLP-2 dual agonists were prepared, their preparation and purification, and analysis in accordance with the guidelines in Patent Application Publication WO2018 / 104561, which are detailed, for example, in Examples 1-4. [Examples]

[0246] k. EC of GLP-1R and GLP-2R 50 Measurement value Creation of cell lines expressing the human GLP-1 receptor. cDNA encoding the human glucagon-like peptide 1 receptor (GLP-1R) (primary accession number P43220) was cloned from cDNA BC112126 (MGC:138331 / IMAGE:8327594). The GLP-1-R encoding DNA was amplified by PCR using primers encoding terminal restriction sites for subcloning. The 5' terminal primer additionally encoded a nearby Kozak consensus sequence to ensure efficient translation. The fidelity of the GLP-1-R encoding DNA was confirmed by DNA sequencing. The PCR product encoding GLP-1-R was subcloned into a mammalian expression vector containing a neomycin (G418) resistance marker. The GLP-1-R encoding mammalian expression vector was transfected into HEK293 cells using a standard calcium phosphate transfection method. 48 hours after transfection, cells were seeded for limiting dilution cloning and selected using 1 mg / ml G418 in culture medium. After 3 weeks of G418 selection, clones were picked and tested in a functional GLP-1 receptor efficacy assay as described below. One clone was selected for use in compound profiling.

[0247] Creation of cell lines expressing the human GLP-2 receptor hGLP2-R was purchased as Image clone:5363415(11924-I17) from MRC-geneservice, Babraham, Cambridge. For subcloning into mammalian expression vectors, primers for subcloning were obtained from DNA-Technology, Risskov, Denmark. The 5' and 3' primers used in the PCR reaction contained terminal restriction sites for cloning, and the context of the 5' primer was modified to Kozak consensus without altering the sequence of the product encoded by the ORF. A standard PCR reaction was performed using Image clone5363415(11924-I17) as a template, with the above-mentioned primers and polymerase Herculase II Fusion, in a total volume of 50 μl. The resulting PCR product was purified using GFX PCR and Gel band purification kits, digested with restriction enzymes, and cloned into mammalian expression vectors using a Rapid DNA ligation kit. Ligation was performed to transform XL10 Gold Ultra competent cells, and colonies were picked for DNA generation using the Endofree Plasmid maxi kit. Subsequent sequencing analysis was performed by MWG Eurofins, Germany. The clone was identified as the hGLP-2(1-33) receptor splice mutant rs17681684.

[0248] HEK293 cells were transfected using the Lipofectamine PLUS transfection method. The day before transfection, HEK293 cells were placed in two T75 flasks, 2 × 10⁶ cells each. 6Cells were seeded at a density of 100 cells / T75 flask in antibiotic-free cell culture medium. On the day of transfection, cells were washed with 1×DPBS, the medium was replaced with Optimem to a volume of 5 mL / T75 flask, and the Lipofectamine-plasmid complex was gently added dropwise to the cells in the T75 flask. After 3 hours, the medium was replaced with growth medium, and after 24 hours, it was replaced again with growth medium supplemented with 500 μg / mL of G418. After 4 weeks in G418 selection, clones were picked and tested in a functional GLP-2 receptor efficacy assay as described below. One clone was selected for use in compound profiling.

[0249] GLP-1R and GLP-2 receptor efficacy assay. The cAMP response to GLP1 and GLP2 receptor activation was quantified using the Perkin Elmer cAMP AlphaScreen® assay. Exendin-4 was used as the reference compound for GLP1 receptor activation, and teduglutide was used as the reference compound for GLP2 receptor activation. Data from test compounds that induce intracellular proliferation of cAMP were normalized to positive and negative controls (vehicles), and the EC2 response curve was obtained from the concentration-response curve. 50 The maximum response was also calculated. The results are listed in Table 1.

[0250] The following reference compounds A and B were also synthesized. A Hy-H[Aib]DGSFSSELATILD[K([17-carboxy-heptadecanoyl]-isoGlu)]QAARDFIAWLIQHKITD-OH B Hy-H[Aib]EGSFSSELATILD[K([17-carboxy-heptadecanoyl]-isoGlu)]QAARDFIAWLIQHKITD-OH

[0251] [Table 2] JPEG0007860224000014.jpg140149 [Examples]

[0252] l. Phase 1a clinical trial of compound 18 with single-dose dose escalation (SAD). A single-dose dose-escalation Phase 1a clinical trial was conducted for compound 18 to investigate the safety of single-dose subcutaneous injections in the range of 0.02 mg to 7.5 mg in healthy human subjects.

[0253] Clinical trial design The Phase 1a trial was the first human, randomized, double-blind, placebo-controlled single-dose dose escalation trial to evaluate the safety, tolerance, pharmacokinetics, and pharmacodynamics of a single subcutaneous dose of compound 18 in healthy human subjects.

[0254] Eight cohorts (dose levels: 0.02, 0.07, 0.2, 0.6, 1.5, 3.0, 6.0, and 7.5 mg) were used in this initial human trial. Eight subjects were assigned to the following escalating dose levels: 0.02, 0.07, 0.2, 0.6, 1.5, 3.0, 6.0, and 7.5 mg. Subjects were randomized in a 3:1 ratio within each cohort, resulting in two subjects in placebo (PBO) and six in the active drug in each cohort, as shown in Table 3 below. Safety assessments were performed after each cohort. Formulations of compound 18 and placebo are shown in Table 2 below.

[0255] [Table 3]

[0256] [Table 4]

[0257] [Table 5]

[0258] Table 4 shows the baseline characteristics of the subjects.

[0259] Adverse events (AEs) were reported by asking open-ended, non-leading questions in accordance with the protocol: 9.2 Collection, recording, and reporting of adverse events All events that meet the definition of an adverse event (AE) must be collected and reported from the first trial-related activity after the subject signs informed consent until the end of the post-treatment follow-up period. Subjects must be questioned about AEs during each contact with the site (in-person visit or telephone call). All AEs, whether observed by the principal investigator or reported by the subject, must be documented and evaluated by the principal investigator. Where possible, the principal investigator should record a diagnosis. If a diagnosis cannot be made, the principal investigator should record each sign and symptom as an individual adverse event (AE). All adverse events (AEs) must be documented by the principal investigator. One single adverse event form must be used for each AE, from its onset to its resolution. For serious adverse events (SAEs), a separate serious adverse event form must also be completed.

[0260] The safety data (incidence / number of subjects) for subjects in the 0.02 mg to 7.5 mg cohort are shown in Table 5 below.

[0261] [Table 6]

[0262] In this trial, half of the subjects (3 / 6) receiving a dose of 1.5 mg of compound 18 reported decreased appetite in their dose cohort, and this was collected as an adverse event. This continued across subsequent cohorts (3.0–6.0 mg of compound 18), and in the final cohort (7.5 mg), all subjects receiving compound 18 reported this. The adverse event of decreased appetite can be interpreted as a marker of the satiety effect of compound 18. Gastrointestinal adverse events related to nausea and vomiting were reported only in the 3.0 mg cohort and cohorts receiving higher doses than 3.0 mg.

[0263] The observation that subjects administered compound 18 experienced decreased appetite without nausea or vomiting was completely unexpected, considering the nausea and vomiting side effects widely observed with GLP-1 agonist administration.

[0264] The data obtained with compound 18 suggest that the effect on appetite suppression occurs (at low doses) before nausea and vomiting occur. This is in contrast to clinical trials with semaglutide, where gastrointestinal adverse events occur (at low doses) before a decrease in satiety.

[0265] This suggests that compound 18 may have a better safety profile with respect to gastrointestinal adverse events in indications where appetite suppression is desired. [Examples]

[0266] m. Plasma half-life in a single-dose dose escalation (SAD) Phase 1a clinical trial. Blood sampling to determine the plasma concentration of compound 18 was performed at scheduled time points during the Phase Ia trial (outlined in Example 2). The concentration of compound 18 in plasma was measured using a validated LC-MS / MS assay. Pharmacokinetic (PK) endpoints for compound 18 were derived from individual concentration profiles (with 1 hour as the unit of time). For PK analysis, compound 18 concentrations were supplied in nmol / L units from the analytical laboratory. The mean measured concentration per dose level is shown in Figure 1.

[0267] λ z To determine this, the logarithm of the plasma compound 18 concentrations was used as the response variable, C max Linear regression was performed using at least three reasonable concentration measurements from the later terminal period. (The exact number of data points depends on the best fit.) max This point can be affected by absorption still occurring from the injection site, λ z It is not included in the calculation.

[0268] Plasma compound 18 profiles elimination half-life (terminal elimination half-life) (t 1 / 2 The following formula was used to calculate: t 1 / 2 =ln2 / λ z

[0269] As shown in Table 6, the calculated average half-life of compound 18 after a single dose is in the range of 110–135. This would be appropriate for once-weekly administration in humans.

[0270] [Table 7] [Examples]

[0271] n. Multi-ascending dose (MAD) design A single-dose dose-escalation Phase 1a trial will be conducted for compound 18 to investigate the safety of repeated subcutaneous injections at various escalating doses in healthy human subjects. This trial will be the first human, randomized, double-blind, placebo-controlled repeated-dose dose-escalation trial to evaluate the safety, tolerance, pharmacokinetics, and pharmacodynamics of repeated subcutaneous doses of compound 18 in healthy human subjects.

[0272] The test design is shown in Figure 2.

[0273] Four cohorts will be conducted. Ten subjects will be assigned to the following escalating dose levels: 4 × 1.0 mg, 4 × 2.25 mg, 4 × 3.5 mg, and 1 × 3.5 mg + 3 × 6.0 mg. Subjects will be randomized within each cohort, with 3 subjects receiving placebo (PBO) and 7 receiving the active drug in each cohort. Safety assessments will be conducted after each cohort. The formulations of compound 18 and placebo are shown in Table 2 above. The medication regimens for each cohort are shown in Table 7.

[0274] [Table 8]

[0275] Adverse events (AEs) are reported by asking open-ended, non-leading questions in accordance with the protocol: 9.2 Collection, recording, and reporting of adverse events All events that meet the definition of an adverse event (AE) must be collected and reported from the first trial-related activity after the subject signs informed consent until the end of the post-treatment follow-up period. Subjects must be questioned about AEs during each contact with the site (in-person visit or telephone call). All AEs, whether observed by the principal investigator or reported by the subject, must be documented and evaluated by the principal investigator. Where possible, the principal investigator should record a diagnosis. If a diagnosis cannot be made, the principal investigator should record each sign and symptom as an individual adverse event (AE). All adverse events (AEs) must be documented by the principal investigator. One single adverse event form must be used for each AE, from its onset to its resolution. For serious adverse events (SAEs), a separate serious adverse event form must also be completed. [Examples]

[0276] o. Repeated dose escalation (MAD) design A repeated dose escalation Phase 1b clinical trial was conducted for compound 18 to investigate the safety of repeated subcutaneous injections at various escalating doses in healthy human subjects. The trial was a randomized, double-blind, placebo-controlled repeated dose escalation study evaluating the safety, tolerance, pharmacokinetics, and pharmacodynamics of repeated subcutaneous doses of compound 18 in healthy human subjects.

[0277] The test design is shown in Figure 2.

[0278] Four cohorts were administered subcutaneously once a week for four doses. Each cohort, consisting of 10 subjects, was randomized to either placebo (n=3) or one of the following active repeated dose escalation levels (n=7): four weekly 1.0 mg injections, four weekly 2.25 mg injections, four weekly 3.5 mg injections, and one weekly 3.5 mg injection followed by three weekly 6.0 mg injections. The formulations of compound 18 and placebo are shown in Table 2 of Example 2 above. The drug administration for each cohort is shown in Table 8.

[0279] [Table 9]

[0280] Adverse events (AEs) were reported by asking open-ended, non-leading questions in accordance with the protocol: 9.2 Collection, recording, and reporting of adverse events All events that meet the definition of an adverse event (AE) must be collected and reported from the first trial-related activity after the subject signs informed consent until the end of the post-treatment follow-up period. Subjects must be questioned about AEs during each contact with the site (in-person visit or telephone call). All AEs, whether observed by the principal investigator or reported by the subject, must be documented and evaluated by the principal investigator. Where possible, the principal investigator should record a diagnosis. If a diagnosis cannot be made, the principal investigator should record each sign and symptom as an individual adverse event (AE). All adverse events (AEs) must be documented by the principal investigator. One single adverse event form must be used for each AE, from its onset to its resolution. For serious adverse events (SAEs), a separate serious adverse event form must also be completed. [Examples]

[0281] p. Repeated dose escalation Phase 1b clinical trial of compound 18 The design of this test is outlined in Example 5.

[0282] Table 9 shows the baseline characteristics of the subjects.

[0283] [Table 10]

[0284] Table 10 below shows the safety data (incidence / number of subjects) for subjects who received 4×1.0mg to 1×3.5mg + 3×6.0mg and placebo.

[0285] [Table 11]

[0286] The safety data collected in this clinical trial support the findings in the SAD trial described in Example 2. At low doses (2.25 mg and 3.5 mg of compound 18), decreased appetite was reported in 3 out of 7 subjects (3 out of 7 subjects) and 2 out of 7 subjects, respectively, while only one subject reported nausea. At the highest dose, most subjects (6 out of 7 subjects) reported decreased appetite, but nausea and vomiting were also frequently reported. The adverse event of decreased appetite after administration of compound 18 can be interpreted as a marker of the satiety effect of compound 18.

[0287] The observation that appetite decreased after administration of compound 18 at 2.25 mg and 3.5 mg doses, and that associated nausea or vomiting was limited, was completely unexpected considering the widespread side effects of nausea and vomiting observed with GLP-1 agonist administration.

[0288] The data obtained with compound 18 suggest that the effect on appetite suppression occurs before nausea and vomiting occur (at low doses). This is in contrast to the clinical trial with semaglutide (Granhall et al., Clin Pharmacokinet 58, 781-791 (2019)), where gastrointestinal adverse events occurred before appetite suppression (at low doses).

[0289] This suggests that compound 18 may have a better safety profile with respect to gastrointestinal adverse events in indications where appetite suppression is desired.

[0290] Body weight was measured during the study period, and a dose-dependent decrease in body weight was demonstrated. See Figure 3.

[0291] The decrease in appetite is reflected in the reduced food intake measured by the mixed-food breakfast test (Table 11) and the measurement of calorie intake with standard lunch and dinner meals (Table 12).

[0292] The Mixed Meal Test (MMT) was conducted at baseline, 24 hours after administration, after the first dose (day 2), and after the fourth dose (day 23). Meals consisted of fixed nutrient content, and the exact initial amounts of nutrients were weighed by kitchen staff using a laboratory scale with a weighing method. Consumption was managed, leftovers were weighed, and recorded as a percentage of the meal. Adjustments for leftovers on day 2 were made on day 23, and weight differences were calculated in carbohydrates.

[0293] Prescribed lunch and dinner meals were provided at baseline (-1 day) and after the fourth dose of medication (23 days). Consumption was monitored, and leftovers were weighed.

[0294] Table 11 shows the food intake data from the mixed-food trial.

[0295] [Table 12]

[0296] At baseline, the mean percentage of food consumption was 95.8–100%, indicating that participants at all dose levels, including placebo, consumed most of their meals. However, after the first dose, there was a dose-dependent decline in food intake, with the two highest-performing cohorts showing 99.2% and 87.5% food intake, respectively. Furthermore, after the fourth dose, there was a significant decline in food intake at the highest dose level, with consumption at 62.5%.

[0297] Table 12 shows the intake of fixed meals provided for lunch and dinner at baseline and after the fourth dose. This data shows a consistent, dose-dependent decline in intake, similar in magnitude to that observed in the mixed-food trial.

[0298] [Table 13] [Examples]

[0299] Q. Investigate the weight loss associated with compound 18 in a clinical trial. This study investigates the efficacy of compound 18 administered subcutaneously once a week to obese individuals.

[0300] The primary objective is to compare the effects of 4 mg and 6 mg of the compound versus placebo on the percentage change in body weight from baseline during a 12-week treatment period.

[0301] Secondary and exploratory objectives include evaluating the effects of 4 mg and 6 mg of compound 18 versus placebo after 12 weeks of treatment on intestinal barrier function, safety, tolerance, and patient-reported outcomes.

[0302] Test design This trial is a proof-of-concept, randomized, double-blind, placebo-controlled, parallel-group, single-center clinical trial investigating the likelihood of weight loss from compound 18 administered once a week.

[0303] Eligible participants will be randomized to one of three treatment groups.

[0304] [Table 14]

[0305] In total, ≥30 kg / m 2 Fifty-four obese participants (18–75 years old) with a body mass index (BMI) will be randomized to receive either 4 mg of compound 18 or 6 mg of compound 18 (investigational medicinal product; IMP) or a placebo for 12 weeks. To ensure blinding, the placebo group will be split into 4 mg and 6 mg placebo groups, resulting in a randomization ratio of 2:2:1:1. The trial will include a 3-week screening period with a screening visit for eligibility assessment (V1), followed by a randomization visit (V2), a 12-week treatment period, and finally a 4-week follow-up period. IMP will be administered subcutaneously into the abdomen once a week from week 0 (V2) to week 12 (V14) (Table 14).

[0306] IMP is initiated at 2 mg once weekly, and titrated up by 2 mg every three weeks until the respective investigational dose is reached in each group (Figure 4). Thereafter, participants will be maintained at that dose level for the remainder of the trial (from weeks 3 and 6 for the 4 mg and 6 mg doses, respectively). However, to reduce withdrawal in cases of low tolerance to IMP, the principal investigator may postpone or downtitrate uptitations if deemed necessary for participant retention or safety. The trial schedule consists of five on-site visits, including screening, randomization, and a safety follow-up visit (four weeks after end of treatment (EOT)), in addition to a minimum of 10 telephone consultations. Therefore, the maximum trial duration is 16 weeks. A maximum of n=7 participants from each treatment group (total n=21 participants) can participate in this sub-study.

[0307] [Table 15]

[0308] The endpoints of the clinical study are shown below in Table 15.

[0309] [Table 16]

[0310] The principal investigator is responsible for the detection, documentation, recording, and monitoring of all adverse events (AEs). All AEs occurring from the time of signed informed consent (V1) until the completion of the study period (V15) will be registered as shown in Table 14. Participants will be instructed to record AEs in a logbook between site visits, and research staff will ask about AEs in an open and non-inductive format during weekly telephone visits. All AEs will be assessed by the principal investigator for severity and their relationship to adverse events (IMPs). All types of AEs will be recorded in a case record form (CRF).

Claims

1. A pharmaceutical composition comprising Hy-H[Aib]EGSFTSELATILD[K([17-carboxy-heptadecanoyl]-isoGlu)]QAARDFIAWLIQHKITD-OH (compound 18), a GLP-1 / GLP-2 dual agonist or a pharmaceutically acceptable salt or solvate thereof, for use in methods of reducing or preventing weight gain, reducing food intake, reducing appetite, promoting weight loss, or treating obesity, morbid obesity, obesity-related gallbladder disease, or obesity-induced sleep apnea, The method includes the step of administering the dual agonist to a patient in a dose of 1.5 mg to 10.0 mg. The aforementioned pharmaceutical composition.

2. The pharmaceutical composition for use according to claim 1, wherein the method comprises the step of administering a dual agonist to a patient in a dose of 1.5 mg to 8.0 mg.

3. The pharmaceutical composition for use according to claim 1, wherein the method comprises the step of administering a dual agonist to a patient in a dose of 1.5 to 7.5 mg, 1.5 to 6.0 mg, 1.5 to 4.0 mg, or 1.5 to 3.5 mg.

4. A pharmaceutical composition for use according to claim 1, wherein the method comprises the step of administering a dual agonist to a patient in a dose of 2.0 to 7.5 mg, 2.0 to 6.0 mg, 2.0 to 4.0 mg, 2.0 to 3.5 mg, or 2.25 to 3.5 mg.

5. A pharmaceutical composition for use according to claim 1, wherein the method comprises the step of administering a dual agonist to a patient in doses of 1.5 mg, 2.0 mg, 2.25 mg, 2.5 mg, 3.0 mg, 3.5 mg, 4.0 mg, 4.5 mg, 5.0 mg, 5.5 mg, 6.0 mg, 6.5 mg, 7.0 mg, 7.5 mg, 8.0 mg, 9.0 mg, or 10.0 mg.

6. The pharmaceutical composition for use according to claim 1, wherein the method comprises the step of administering to a patient one, two, three, or four low doses of a dual agonist or a pharmaceutically acceptable salt or solvate thereof, and then at least one high dose of the dual agonist or a pharmaceutically acceptable salt or solvate thereof.

7. A pharmaceutical composition for use according to claim 6, wherein the low dose is 1.5 mg to 3.5 mg.

8. A pharmaceutical composition for use according to claim 6, wherein the high dose is 6.0 mg to 8.5 mg.

9. A pharmaceutical composition for use according to any one of claims 1 to 8, wherein the method comprises the step of administering a dual agonist to a patient by injection.

10. The pharmaceutical composition for use according to claim 9, wherein the method comprises the step of administering a dual agonist to a patient by subcutaneous injection.

11. A pharmaceutical composition for use according to any one of claims 1 to 8, wherein the patient is a human being.

12. A pharmaceutical composition for use according to any one of claims 1 to 8, wherein the patient does not experience nausea and / or vomiting as a side effect after administration of a dual agonist.

13. A pharmaceutical composition for use according to any one of claims 1 to 8, wherein the method comprises administering a dual agonist once a week.

14. A pharmaceutical composition for use according to any one of claims 1 to 8, wherein a dual agonist or a pharmaceutically acceptable salt or solvate thereof is mixed with a carrier.

15. A pharmaceutical composition for use according to any one of claims 1 to 8, which is an isotonic parenteral composition.

16. a) A phosphate buffering agent component in a concentration of 5 mM to 50 mM, a phosphate buffering agent component in a concentration of 10 mM to 40 mM, a 15 mM to 30 mM, or a 20 mM concentration, b) One or more isotonic agents in a concentration of 190 mM to 240 mM, comprising or containing a nonionic isotonic agent, wherein the nonionic isotonic agent is mannitol, and the one or more isotonic agents and A pharmaceutical composition for use according to claim 15, which is an isotonic parenteral composition comprising a solvent, the composition further comprising a solvent The pharmaceutical composition having a pH of 6.0 to 8.2, or a pH of 7.0 to 8.0.

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