Double-Acylated GLP-1 Derivatives with a Linker

Abstract

The invention relates to a derivative of a GLP-1 analogue, which analogue comprises a first K residue at a position corresponding to position 18 of GLP-1(7-37) (SEQ ID NO: 1), a second K residue at another position, and a maximum of twelve amino acid changes as compared to GLP-1(7-37); which derivative comprises two protracting moieties attached to said first and second K residue, respectively, via a linker, wherein the protracting moiety is selected from HOOC—(CH2)x-CO—*, and Chem. 1: HOOC—C6H4-0-(CH2)y-CO—*, Chem. 2: in which x is an integer in the range of 6-18, and y is an integer in the range of 3-17; and the linker comprises *—NH—(CH2)q-CH[(CH2)w-NH2]-CO—*, Chem. 3: wherein q is an integer in the range of 0-5, and w is an integer in the range of 0-5; or a pharmaceutically acceptable salt, amide, or ester thereof. The invention also relates to the pharmaceutical use thereof, for example in the treatment and/or prevention of all forms of diabetes and related diseases, as well as to corresponding novel peptides and side chain intermediates. The derivatives are potent, protracted, and suitable for oral administration.

1 . A GLP-1 analogue which comprises the following changes as compared to GLP-1(7-37) (SEQ ID NO: 1): (a) 7Imp, 8Aib, 18K, 22E, 34Q; (b) 7Imp, 18K, 22E, 25V, 26R, 31K, 34R; or (c) 8Aib, 18K, 19Q, 22E, 34Q; or a pharmaceutically acceptable salt, amide, or ester of any of the analogues of (a)-(c). 
     
     
         2 . A GLP-1 analogue selected from the following analogues of GLP-1(7-37) (SEQ ID NO: 1): (a) 7Imp, 8Aib, 18K, 22E, 34Q (SEQ ID NO: 5); (b) 7Imp, 18K, 22E 25V, 26R, 31K, 34R (SEQ ID NO: 6); or (c) 8Aib, 18K, 19Q, 22E, 34Q (SEQ ID NO: 7); or a pharmaceutically acceptable salt, amide, or ester of any of the analogues of (a)-(c).