Novo Nordisk A/S
Double-acylated GLP-1 derivatives

Abstract:

The invention relates to a derivative of a GLP-1 analogue, which analogue comprises a first K residue and a second K residue, at positions corresponding to position 26, and 37, respectively, of GLP-1(7-37) (SEQ ID NO: 1), and a maximum of eight 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 Chem. 1: HOOC--(CH.sub.2).sub.x--CO--*, and Chem. 2: HOOC--C.sub.6H.sub.4--O--(CH.sub.2).sub.y--CO--*, in which x is an integer in the range of 8-16, and y is an integer in the range of 6-13; and the linker comprises Chem. 3: *--NH--(CH.sub.2).sub.q--CH[(CH.sub.2).sub.w--NR.sub.1R.sub.2]--CO--*, which is connected at its CO--* end to the epsilon amino group of the first or the second K residue of the GLP-1 analogue, and wherein q is an integer in the range of 0-5, R.sub.1 and R.sub.2 independently represent *--H or *--CH.sub.3, 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 peptide and linker intermediates. The derivatives are potent, stable, protracted, and suitable for oral administration.