Amylin receptor agonists
The invention relates to a compound comprising an amylin receptor agonist. The invention also relates to a pharmaceutical composition, suitable for but not limited to oral administration, which comprises such a compound. The compound and pharmaceutical composition comprising it may be used for the medical treatment of subjects with overweight, obesity and associated co-morbidities.
1. An amylin receptor agonist according to Formula I (SEQ ID NO: 36):
AX 2 X 3 LX 5 TX 7 QTX 10 RLAEFLHHX 19 X 20 X 21 X 22 FGX 25 IX 27 X 28 X 29 TX 31 VGX 34 X 35 TX 37 ,
wherein
X 2 is S or G,
X 3 is H, S, Q, or E,
X 5 is S,
X 7 is A,
X 10 is Q or A,
X 19 is S or absent,
X 20 is S or absent,
X 21 is D or absent,
X 22 is N, P or absent,
X 25 is A or P,
X 27 is L or P,
X 28 is S or P,
X 29 is S or P,
X 31 is D,
X 34 is S or P,
X 35 is N, D, or E, and
X 37 is P.
2. The amylin receptor agonist according to claim 1 ,
wherein
X 27 X 28 X 29 is selected from LPP or PSS.
3. The amylin receptor agonist according to claim 2 , comprising a peptide selected from the following:
(SEQ ID NO: 13)
AGELSTAQTARLAEFLHHFGPILPPTDVGSETP,
(SEQ ID NO: 16)
ASQLSTAQTARLAEFLHHSSDNFGPILPPTDVGSNTP,
and
(SEQ ID NO: 19)
ASHLSTAQTARLAEFLHHSSDPFGAIPSSTDVGPDTP,
wherein the peptide comprises a C-terminal amide.
4. The amylin receptor agonist according to claim 1 , further comprising a protraction moiety.
5. The amylin receptor agonist according to claim 4 , wherein the protraction moiety represented by formula (A)-(B) is attached via linker (A) to the alpha position of the A at position 1.
6. The amylin receptor agonist according to claim 5 , wherein the amino acid at position 25 is A or P when the protraction moiety is attached to the A at position 1.
7. The amylin receptor agonist according to claim 5 , wherein protractor (B) of the protraction moiety represented by formula (A)-(B) comprises a C-14 diacid, C-16 diacid, C-18 diacid, or C-20 diacid.
8. The amylin receptor agonist according to claim 5 , wherein the linker (A) of the protraction moiety comprises a moiety according to Chem. 8a:
9. The amylin receptor agonist according to claim 7 , selected from the following:
10. A pharmaceutical composition comprising the amylin receptor agonist according to claim 1 , one or more pharmaceutically acceptable excipients, and/or pharmaceutically acceptable salt, ester, or amide forms thereof.
11. A pharmaceutical composition comprising the amylin receptor agonist peptide according to claim 3 , one or more pharmaceutically acceptable excipients, and/or pharmaceutically acceptable salt, ester, or amide forms thereof.
12. A pharmaceutical composition comprising the amylin receptor agonist according to claim 9 , one or more pharmaceutically acceptable excipients, and/or pharmaceutically acceptable salt, ester, or amide forms thereof.
13. A method of treating diabetes, cardiovascular disease, non-alcoholic steatohepatitis (NASH), cognitive impairment, and/or a Body Mass Index (BMI) of 27 or more, comprising administering to a subject in need of such treatment a pharmaceutically effective amount of the pharmaceutical composition according to claim 10 .
14. A method of treating diabetes, cardiovascular disease, NASH, cognitive impairment, and/or a BMI of 27 or more, comprising administering to a subject in need of such treatment a pharmaceutically effective amount of the pharmaceutical composition according to claim 11 .
15. A method of treating diabetes, cardiovascular disease, NASH, cognitive impairment, and/or a BMI of 27 or more, comprising administering to a subject in need of such treatment a pharmaceutically effective amount of the pharmaceutical composition according to claim 12 .