Glucagon-Like Peptide-1 derivatives and their pharmaceutical use

摘要

The invention relates to protracted Glucagon-Like Peptide-1 (GLP-1) derivatives and therapeutic uses thereof. The GLP-1 derivative of the invention comprises a modified GLP-1(7-37) sequence having a total of 2-12 amino acid modifications, including Glu22 and Arg26, and being derivatised with an albumin binding residue or pegylated in position 18, 20, 23, 30, 31, 34, 36, 37, or 39. These compounds are useful in the treatment or prevention of diabetes type 2 and related diseases. The compounds are potent, stable, have long half-lives, a high affinity of binding to albumin, and/or a high affinity of binding to the extracellular domain of the GLP-1 receptor (GLP-1R), all of which is of potential relevance for the overall aim of achieving long-acting, stable and active GLP-1 derivatives with a potential for once weekly administration.

主权项

1. A GLP-1 derivative which comprises a modified GLP-1(7-37) sequence having:
i) a total of 3-12 amino acid modifications as compared to GLP-1(7-37) (SEQ ID No: 1), including a) a Aib residue at a position equivalent to position 8 of GLP-1(7-37), b) a Glu residue at a position equivalent to position 22 of GLP-1(7-37), and c) an Arg residue at a position equivalent to position 26 of GLP-1(7-37); and ii) which is derivatised with an albumin binding residue or pegylated in a position selected from a position equivalent to position 18, 20, 23, 30, 31, 34, 36, or 37 of GLP-1(7-37).