INCRETIN ANALOGUES AS TRIPLE AGONISTS OF THE GLP-1, GIP, AND GLUCAGON RECEPTORS AND THEIR USES

Claims

The invention relates to incretin analogue compounds that are triple agonists of GLP-1 / GIP / Gcg receptors and their medical use in the treatment and / or prevention of diseases such as dyslipidemia, fatty liver disease, metabolic syndrome, MASH, MAFLD, obesity, and T2DM.

1. A triple agonist of the GLP-1 / GIP / Gcg receptors comprising a peptide, wherein the amino acid sequence of the peptide is: YX 2 QGTFTSDYSIX 13 X 14 DX 16 X 17 AQX 20 AFIEYX 26 X 27 EGGPSSGAPPPS (SEQ ID No. 5), wherein X 2 is Aib, (S)-D3Aib, or (R)-D3Aib, X 13 is αMeL, αD3MeL, αMedhL / αMedhLeu, (D)-αMedhL / (D)-αMedhLeu, αMecpL / αMecpLeu, αMecbL / αMecbLeu, (D)-αMecpL / (D)-αMecpLeu, cpL / cpLeu, or cbL / cbLeu, X 14 is L, cpL, or cbL, X 16 is K, Dab, Orn, OxiK, OxiOrn, or homoK, X 17 is K, Dab, homoK, Orn, OxiK, or OxiOrn, with the distal amino group optionally conjugated by a linker to the *HOOC group of a fatty diacid of the formula *HOOC-(C12-20 alkylene)-COOH, to the *HOOC group of phosphonic acid substituted with a terminal carboxylic acid of the formula *HOOC-(C11-21 alkylene)-PO3H2, or to the *HOOC group of a molecular group *HOOC-(C6-21 alkylene)-B, wherein B = formula (1), R a and R b are each one independently selected from the group of formulas (2);yoyp are each independently selected from 1-6, X20 is Aib, (S)-D3Aib, or (R)-D3Aib, X26 is L, cpL, or cbL, X27 is L, cpL, or cbL, and the S C-terminal amino acid is optionally amidated, or a pharmaceutically acceptable salt thereof.

16. A pharmaceutical composition comprising the triple agonist of the GLP 1 / GIP / Gcg receptors according to any one of claims 1-14 and optionally at least one pharmaceutically acceptable excipient.