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Publication Abstract from PubMed

Liraglutide is an acylated Glucagon-Like Peptide-1 (GLP-1) analog that binds to serum albumin in vivo, and is approved for once daily treatment of diabetes as well as obesity. The aim of the present studies was to design a once-weekly GLP-1 analog by increasing albumin affinity and secure full stability against metabolic degradation. The fatty acid moiety and the linking chemistry to GLP-1 were the key features to secure high albumin affinity and GLP-1 receptor (GLP-1R) potency and in obtaining a prolonged exposure and action of the GLP-1 analog. Semaglutide was selected as the optimal once weekly candidate. Semaglutide has two amino acid substitutions compared to human GLP-1 (Aib8, Arg34) and is derivatized at lysine 26. The GLP-1R affinity of semaglutide (0.38 +/- 0.06 nM) was 3-fold decreased compared to liraglutide, whereas the albumin affinity was increased. The plasma half-life was 46h in mini-pigs following i.v. administration and semaglutide has an MRT of 63.6h after s.c. dosing. Semaglutide is currently in phase 3 clinical testing.

The discovery of the once weekly glucagon like peptide 1 (GLP-1) analog semaglutide.,Lau J, Bloch P, Schaffer L, Pettersson I, Spetzler J, Kofoed J, Madsen K, Knudsen LB, McGuire J, Steensgaard DB, Strauss HM, Gram DX, Knudsen SM, Nielsen FS, Thygesen P, Reedtz-Runge S, Kruse T J Med Chem. 2015 Aug 26. PMID:26308095^[1]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.