HAM
The present invention relates to hAM 15-52 analogues with improved amylin receptor (hAMY3R) potency (hAMY3R-EC 50 ≤250 pM) and which are largely based on the sequence of the human adrenomedullin fragment hAM 15-52 . The invention further relates to hAM 15-52 analogues that are selective amylin receptor (hAMY3R) agonists (hAMY3R-EC 50 ≤250 pM and an hAM1R-EC 50 ≤25 nM) and which are largely based on the sequence of the human adrenomedullin fragment hAM 15-52 . The hAM 15-52 analogues according to the invention maintain the good physical stability of hAM 15-52 . The invention further relates to pharmaceutical compositions comprising such polypeptides and their use in the treatment of a medical condition such as obesity, NASH and/or diabetes.
1. An hAM 15-52 analogue or a pharmaceutically acceptable salt thereof comprising 38 amino acids (X 1 -X 38 ) with an hAMY3R-EC 50 ≤250 μM and an hAM1R-EC 50 ≥25 nM, wherein the amino acid in position X 4 is selected as F, Y, W, T, M, I, A, or C; X 37 is selected as G, Y, S, W, T, Q, P, M, I, H, F, E, A, R, C, or K; X 38 is selected as Hyp, Y, W, T, Q, P, M, I, H, F, E, A, R, or K; X 11 is R, W, or Cit and wherein at least one of the positions X 4 , X 37 or X 38 is not the amino acid present in hAM 15-52 (SEQ ID NO: 1) in said position and further wherein the hAM 15-52 analogue has at least 50% identity to hAM 15-52 (SEQ ID NO: 1).
2. An hAM 15-52 analogue or a pharmaceutically acceptable salt thereof according to claim 1 , wherein the hAM 15-52 analogue has at least 60% identity to hAM 15-52 (SEQ ID NO: 1).
3. An hAM 15-52 analogue according to claim 1 , wherein at least two of the positions X 4 , X 37 , and X 38 is not the amino acid present in hAM 15-52 (SEQ ID NO: 1) in said position.
4. An hAM 15-52 analogue according to claim 1 , wherein X 4 is selected as F, W, M, I, or C.
5. An hAM 15-52 analogue thereof according to claim 1 , wherein X 37 is selected as G, Y, W, P, H, or F.
6. An hAM 15-52 analogue according to claim 1 , wherein X 38 is selected as Hyp, Y, W, M, or F.
7. An hAM 15-52 analogue according to claim 1 , wherein X 17 is selected as W, or H.
8. An hAM 15-52 analogue according to claim 1 , wherein X 11 is R.
9. An hAM 15-52 analogue or a pharmaceutically acceptable salt thereof according to claim 1 , wherein the hAM 15-52 analogue has at least 70% identity to hAM 15-52 (SEQ ID NO: 1).
10. An hAM 15-52 analogue or a pharmaceutically acceptable salt thereof according to claim 1 , wherein the hAM 15-52 analogue has at least 80% identity to hAM 15-52 (SEQ ID NO: 1).