Discovery of the Once-Weekly Glucagon-Like Peptide-1 (GLP-1) Analogue Semaglutide

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• 作者：Jesper Lau ; Paw Bloch ; Lauge Sch盲ffer ; Ingrid Pettersson ; Jane Spetzler ; Jacob Kofoed ; Kjeld Madsen ; Lotte Bjerre Knudsen ; James McGuire ; Dorte Bjerre Steensgaard ; Holger Martin Strauss ; Dorte X. Gram ; Sanne M酶ller Knudsen ; Flemming Seier Nielsen ; Peter Thygesen ; Steffen Reedtz-Runge ; Thomas Kruse
• 刊名：Journal of Medicinal Chemistry
• 出版年：2015
• 出版时间：September 24, 2015
• 年：2015
• 卷：58
• 期：18
• 页码：7370-7380
• 全文大小：488K
• ISSN：1520-4804

文摘

Liraglutide is an acylated glucagon-like peptide-1 (GLP-1) analogue 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 analogue 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 analogue. 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 卤 0.06 nM) was three-fold decreased compared to liraglutide, whereas the albumin affinity was increased. The plasma half-life was 46.1 h in mini-pigs following i.v. administration, and semaglutide has an MRT of 63.6 h after s.c. dosing to mini-pigs. Semaglutide is currently in phase 3 clinical testing.