The invention relates to compounds having agonist activity at the GLP-1 (glucagon-like-peptide 1) and GLP-2 (glucagon-like peptide 2) receptors. The compounds find use, inter alia, in the prophylaxis or treatment of intestinal damage and dysfunction, regulation of body weight, and prophylaxis or tre
The invention relates to compounds having agonist activity at the GLP-1 (glucagon-like-peptide 1) and GLP-2 (glucagon-like peptide 2) receptors. The compounds find use, inter alia, in the prophylaxis or treatment of intestinal damage and dysfunction, regulation of body weight, and prophylaxis or treatment of metabolic dysfunction.
대표청구항▼
1. A GLP-1/GLP-2 dual agonist represented by the formula: R1—X*—U—R2 wherein:R1 is hydrogen (Hy), C1-4 alkyl, acetyl, formyl, benzoyl or trifluoroacetyl;R2 is NH2 or OH;X* is a peptide of formula I: (I)(SEQ ID NO: 3)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
1. A GLP-1/GLP-2 dual agonist represented by the formula: R1—X*—U—R2 wherein:R1 is hydrogen (Hy), C1-4 alkyl, acetyl, formyl, benzoyl or trifluoroacetyl;R2 is NH2 or OH;X* is a peptide of formula I: (I)(SEQ ID NO: 3)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-X33whereinX2 is Aib or G;X5 is S or T;X7 is S or T;X8 is S, E or D;X10 is L, M or V;X11 is A, N or S;X15 is D or EX16 is E, A or G;X17 is Q, E, L or K;X19 is A, V or S;X20 is R or K;X21 is D, L or E;X24 is A, N or S;X27 is I, Y, Q, H or K;X28 is A, E, H, Y, L, K, Q, R or S;X29 is H, Y, K or Q;X33 is D or E;U is absent or a sequence of 1-15 residues, each independently selected from K and k;and wherein at least one of X5 and X7 is T;or a pharmaceutically acceptable salt thereof. 2. A dual agonist or pharmaceutically acceptable salt thereof according to claim 1 wherein: X2 is Aib;X5 is S or T;X7 is S or T;X8 is S or D;X10 is L;X11 is A or S;X15 is D or EX16 is E or G;X17 is Q or K;X19 is A or S;X20 is R;X21 is D or E;X24 is A, N or S;X27 is I, Y, Q or K;X28 is A, E, H, Y or L;X29 is H, Y or Q; andX33 is D. 3. A dual agonist or pharmaceutically acceptable salt thereof according to claim 1 wherein X2 is Aib, X8 is S, X7 is T, X5 is T, X29 is H and/or X27 is I. 4-8. (canceled) 9. A dual agonist or pharmaceutically acceptable salt thereof according to claim 1 wherein X27 is Q and X29 is Q or optionally wherein X28 is A and X29 is H, oroptionally wherein X28 is E and X29 is H. 10-11. (canceled) 12. A dual agonist or pharmaceutically acceptable salt thereof according to claim 1 wherein X11 is A, and/or, X16 is E and X17 is Q, and/or X16 is G and X17 is K. 13. (canceled) 14. A dual agonist or pharmaceutically acceptable salt thereof according to claim 1 wherein: X11 is S and X15 is E;X11 is Sand X19 is S;X11 is S and X21 is E;X15 is E and X19 is S;X15 is E and X21 is E;X11 is S, X15 is E and X19 is S;X11 is S, X15 is E and X21 is E;X11 is S, X19 is S and X21 is E;X15 is E, X19 is S and X21 is E; orX11 is S, X15 is E, X19 is S. and X21 is E. 15. A dual agonist or pharmaceutically acceptable salt thereof according claim 1 wherein residues X8-X24 contain a maximum of four changes compared to the sequence SELATILDEQAARDFIA (SEQ ID NO: 4). 16. (canceled) 17. A dual agonist or pharmaceutically acceptable salt thereof according to claim 1 wherein the residues at X27-X29 have a sequence selected from: IAH;HAH;QAH;YAH;IAQ;MY;YEH;IQH;IKH;IRH;ISH;HQH;QAQ;HAQ;YAH;YRH;KAH;KSY;KEQ;IEH; andILH. 18. A dual agonist or pharmaceutically acceptable salt thereof according to claim 1 wherein X* is a peptide of formula II: (II)(SEQ ID NO: 5)H[Aib]EG-X5-F-X7-SELATILDEQAARDFIAWLI-X28-X29-KITDwhereinX5 is S or T;X7 is S or T;X28 is A, E, H, Y or L;X29 is H, Y or 0;and wherein at least one of X5 and X7 is T,optionally wherein X5 is S and X7 is T;X5 is T and X7 is S; orX5 is T and X7 is T. 19. (canceled) 20. A dual agonist or pharmaceutically acceptable salt thereof according to claim 1 wherein U is absent or U is a peptide sequence of 1-15 lysine residues, optionally 1-10 lysine residues, wherein said U optionally is K3, K4, K5, K6, K7, k3, k4, k5, k6 or k7. 21-22. (canceled) 23. A dual agonist or pharmaceutically acceptable salt thereof according to claim 1 wherein R1 is Hy and/or R2 is OH. 24. A dual agonist or pharmaceutically acceptable salt thereof according to claim 1 wherein X* has the sequence: (SEQ ID NO: 6)H[Aib]EGSFTSELATILDEQAARDFIAWLIAHKITD;(SEQ ID NO: 7)H[Aib]EGTFSSELATILDEQAARDFIAWLIAHKITD;(SEQ ID NO: 8)H[Aib]EGTFTSELATILDEQAARDFIAWLIAHKITD;(SEQ ID NO: 9)H[Aib]EGSFTSELATILDEQAARDFIAWLIEHKITD;(SEQ ID NO: 10)H[Aib]EGTFTSELATILDEQAARDFIAWLIEHKITD;(SEQ ID NO: 11)H[Aib]EGSFTSELATILDEQAARDFIAWLIHHKITD;(SEQ ID NO: 12)H[Aib]EGSFTSELATILDEQAARDFIAWLIYHKITD;(SEQ ID NO: 13)H[Aib]EGSFTSELATILDEQAARDFIAWLILHKITD;(SEQ ID NO: 14)H[Aib]EGTFTDELATILDEQAARDFIAWLIAHKITD;(SEQ ID NO: 15)H[Aib]EGTFTSELSTILDEQAARDFIAWLIAHKITD;(SEQ ID NO: 16)H[Aib]EGTFTSELATILDGKAARDFIAWLIAHKITD;(SEQ ID NO: 17)H[Aib]EGTFTSELATILDEQAARDFIAWLHAHKITD;(SEQ ID NO: 18)H[Aib]EGTFTSELATILDEQAARDFIAWLQAHKITD;(SEQ ID NO: 19)H[Aib]EGTFTSELATILDEQAARDFIAWLYAHKITD;(SEQ ID NO: 20)H[Aib]EGTFTSELATILDEQAARDFIAWLIQHKITD;(SEQ ID NO: 21)H[Aib]EGTFTSELATILDEQAARDFIAWLIKHKITD;(SEQ ID NO: 22)H[Aib]EGTFTSELATILDEQAARDFIAWLIRHKITD;(SEQ ID NO: 23)H[Aib]EGTFTSELATILDEQAARDFIAWLISHKITD;(SEQ ID NO: 24)H[Aib]EGTFTSELATILDEQAARDFIAWLIAQKITD;(SEQ ID NO: 25)H[Aib]EGTFTSELATILDEQAARDFIAWLIAYKITD;(SEQ ID NO: 26)H[Aib]EGTFTSELATILDEQAARDFIAWLHQHKITD;(SEQ ID NO: 27)H[Aib]EGSFTSELATILDEQAARDFIAWLHAHKITD;(SEQ ID NO: 28)H[Aib]EGSFTSELATILDEQAARDFIAWLYEHKITD;(SEQ ID NO: 29)H[Aib]EGSFTSELATILDEQAARDFIAWLQAHKITD;(SEQ ID NO: 30)H[Aib]EGSFTSELATILDEQAARDFIAWLIAQKITD;(SEQ ID NO: 31)H[Aib]EGTFTSELATILDEQAARDFIAWLQAQKITD;(SEQ ID NO: 32)H[Aib]EGTFTSELSTILDEQAARDFIAWLHAQKITD;(SEQ ID NO: 33)H[Aib]EGSFTSELATILDEQAARDFIAWLYAHKITD;(SEQ ID NO: 34)H[Aib]EGTFTDELATILDEQAARDFIAWLQAQKITD;(SEQ ID NO: 35)H[Aib]EGSFTSELATILDEQAARDFIAWLYRHKITD;(SEQ ID NO: 36)H[Aib]EGSFTSELATILDGKAARDFIAWLIAHKITD;(SEQ ID NO: 37)H[Aib]EGTFSSELATILDGKAARDFIAWLIAHKITD;(SEQ ID NO: 38)H[Aib]EGTFTSELATILDEQAARDFINWLIAHKITD;(SEQ ID NO: 39)H[Aib]EGTFTSELATILDEQAARDFISWLIAHKITD;(SEQ ID NO: 40)H[Aib]EGTFTSELATILDEQAARDFINWLKAHKITD;(SEQ ID NO: 41)H[Aib]EGTFTSELATILDEQAARDFINWLKSYKITD;(SEQ ID NO: 42)H[Aib]EGTFTSELATILDEQAARDFINWLKEQKITD;(SEQ ID NO: 43)HGEGTFTSELATILDEQAARDFIAWLIAHKITD;(SEQ ID NO: 44)H[Aib]EGTFSSELSTILEEQASREFIAWLIAHKITE;(SEQ ID NO: 45)HGEGSFSSELATILDEQAARDFIAWLIQHKITD;or(SEQ ID NO: 46)H[Aib]EGSFSSELATILDEQAARDFIAWLIQHKITD. 25. A dual agonist or pharmaceutically acceptable salt thereof according to claim 24 which is: (Compound 1)Hy-H[Aib]EGSFTSELATILDEQAARDFIAWLIAHKITD-OH;(Compound 2)Hy-H[Aib]EGTFSSELATILDEQAARDFIAWLIAHKITD-OH;(Compound 3)Hy-H[Aib]EGTFTSELATILDEQAARDFIAWLIAHKITD-OH;(Compound 4)Hy-H[Aib]EGSFTSELATILDEQAARDFIAWLIEHKITD-OH;(Compound 5)Hy-H[Aib]EGTFTSELATILDEQAARDFIAWLIEHKITD-OH;(Compound 6)Hy-H[Aib]EGSFTSELATILDEQAARDFIAWLIHHKITD-OH;(Compound 7)Hy-H[Aib]EGSFTSELATILDEQAARDFIAWLIYHKITD-OH;(Compound 8)Hy-H[Aib]EGSFTSELATILDEQAARDFIAWLILHKITD-OH;(Compound 9)Hy-H[Aib]EGTFTDELATILDEQAARDFIAWLIAHKITD-OH;(Compound 10)Hy-H[Aib]EGTFTSELSTILDEQAARDFIAWLIAHKITD-OH;(Compound 11)Hy-H[Aib]EGTFTSELATILDGKAARDFIAWLIAHKITD-OH;(Compound 12)Hy-H[Aib]EGTFTSELATILDEQAARDFIAWLHAHKITD-OH;(Compound 13)Hy-H[Aib]EGTFTSELATILDEQAARDFIAWLQAHKITD-OH;(Compound 14)Hy-H[Aib]EGTFTSELATILDEQAARDFIAWLYAHKITD-OH;(Compound 15)Hy-H[Aib]EGTFTSELATILDEQAARDFIAWLIQHKITD-OH;(Compound 16)Hy-H[Aib]EGTFTSELATILDEQAARDFIAWLIKHKITD-OH;(Compound 17)Hy-H[Aib]EGTFTSELATILDEQAARDFIAWLIRHKITD-OH;(Compound 18)Hy-H[Aib]EGTFTSELATILDEQAARDFIAWLISHKITD-OH;(Compound 19)Hy-H[Aib]EGTFTSELATILDEQAARDFIAWLIAQKITD-OH;(Compound 20)Hy-H[Aib]EGTFTSELATILDEQAARDFIAWLIAYKITD-OH;(Compound 21)Hy-H[Aib]EGTFTSELATILDEQAARDFIAWLHQHKITD-OH;(Compound 22)Hy-H[Aib]EGSFTSELATILDEQAARDFIAWLHAHKITD-OH;(Compound 23)Hy-H[Aib]EGSFTSELATILDEQAARDFIAWLYEHKITD-OH;(Compound 24)Hy-H[Aib]EGSFTSELATILDEQAARDFIAWLQAHKITD-OH;(Compound 25)Hy-H[Aib]EGSFTSELATILDEQAARDFIAWLIAQKITD-OH;(Compound 26)Hy-H[Aib]EGTFTSELATILDEQAARDFIAWLQAQKITD-OH;(Compound 27)Hy-H[Aib]EGTFTSELSTILDEQAARDFIAWLHAQKITD-OH;(Compound 28)Hy-H[Aib]EGSFTSELATILDEQAARDFIAWLYAHKITD-OH;(Compound 29)Hy-H[Aib]EGTFTDELATILDEQAARDFIAWLQAQKITD-OH;(Compound 30)Hy-H[Aib]EGSFTSELATILDEQAARDFIAWLYRHKITD-OH;(Compound 31)Hy-H[Aib]EGSFTSELATILDGKAARDFIAWLIAHKITD-OH;(Compound 32)Hy-H[Aib]EGTFSSELATILDGKAARDFIAWLIAHKITD-OH;(Compound 33)Hy-H[Aib]EGTFTSELATILDEQAARDFINWLIAHKITD-OH;(Compound 34)Hy-H[Aib]EGTFTSELATILDEQAARDFISWLIAHKITD-OH;(Compound 35)Hy-H[Aib]EGTFTSELATILDEQAARDFINWLKAHKITD-OH;(Compound 36)Hy-H[Aib]EGTFTSELATILDEQAARDFINWLKSYKITD-OH;(Compound 37)Hy-H[Aib]EGTFTSELATILDEQAARDFINWLKEQKITD-OH;(Compound 38)Hy-HGEGTFTSELATILDEQAARDFIAWLIAHKITD-OH;(Compound 39)Hy-H[Aib]EGTFSSELSTILEEQASREFIAWLIAHKITE-OH;(Compound 40)Hy-HGEGSFSSELATILDEQAARDFIAWLIQHKITD-[NH2];or(Compound 41)Hy-H[Aib]EGSFSSELATILDEQAARDFIAWLIQHKITD-OH. 26. A composition comprising a dual agonist according to claim 1, or a pharmaceutically acceptable salt thereof, in admixture with a carrier and optionally further comprising excipient or vehicle, optionally wherein the carrier is a pharmaceutically acceptable carrier. 27-33. (canceled) 34. A method of increasing intestinal mass, improving intestinal function, increasing intestinal blood flow, or repairing intestinal damage or dysfunction in a subject in need thereof, the method comprising administering a dual agonist according to claim 1 to the subject. 35. A method of prophylaxis or treatment of malabsorption, ulcers, short-bowel syndrome, cul-de-sac syndrome, inflammatory bowel disease, irritable bowel syndrome, pouchitis, celiac sprue, tropical sprue, hypogammaglobulinemic sprue, mucositis induced by chemotherapy or radiation therapy, diarrhea induced by chemotherapy or radiation therapy, low grade inflammation, metabolic endotoxemia, necrotising enterocolitis, primary biliary cirrhosis, hepatitis, fatty liver disease, or gastrointestinal side-effects of inflammatory conditions in a subject in need thereof, the method comprising administering a dual agonist according to claim 1 to the subject. 36. A method of reducing or inhibiting weight gain, reducing gastric emptying or intestinal transit, reducing food intake, reducing appetite, or promoting weight loss in a subject in need thereof, the method comprising administering a dual agonist according to claim 1 to the subject. 37. A method of prophylaxis or treatment of obesity, morbid obesity, obesity-linked gallbladder disease, obesity-induced sleep apnea, inadequate glucose control, glucose tolerance, dyslipidemia, diabetes, pre-diabetes, metabolic syndrome or hypertension in a subject in need thereof, the method comprising administering a dual agonist according to claim 1 to the subject. 38-41. (canceled)
※ AI-Helper는 부적절한 답변을 할 수 있습니다.