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

• Published in: Journal of medicinal chemistry Vol. 58; no. 18; pp. 7370 - 7380
• Main Authors: Lau, Jesper, Bloch, Paw, Schäffer, Lauge, Pettersson, Ingrid, Spetzler, Jane, Kofoed, Jacob, Madsen, Kjeld, Knudsen, Lotte Bjerre, McGuire, James, Steensgaard, Dorte Bjerre, Strauss, Holger Martin, Gram, Dorte X, Knudsen, Sanne Møller, Nielsen, Flemming Seier, Thygesen, Peter, Reedtz-Runge, Steffen, Kruse, Thomas
• Format: Journal Article
• Language: English
• Published: WASHINGTON American Chemical Society 24.09.2015; Amer Chemical Soc
• Subjects: Administration, Intravenous; Animals; Cell Line; Chemistry, Medicinal; Cricetinae; Crystallography, X-Ray; Glucagon-Like Peptide 1 - administration & dosage; Glucagon-Like Peptide 1 - analogs & derivatives; Glucagon-Like Peptide 1 - chemistry; Glucagon-Like Peptide 1 - pharmacology; Glucagon-Like Peptide-1 Receptor - agonists; Glucagon-Like Peptide-1 Receptor - metabolism; Glucagon-Like Peptides - administration & dosage; Glucagon-Like Peptides - chemistry; Glucagon-Like Peptides - pharmacology; Half-Life; Humans; Injections, Subcutaneous; Life Sciences & Biomedicine; Liraglutide - pharmacology; Male; Mice, Obese; Models, Molecular; Pharmacology & Pharmacy; Rats, Sprague-Dawley; Science & Technology; Structure-Activity Relationship; Swine; Swine, Miniature; FATTY-ACID-BINDING; DAILY LIRAGLUTIDE; PHARMACOKINETICS; SAFETY; EXENATIDE; HEALTHY MALE-SUBJECTS; OPEN-LABEL; PHARMACODYNAMICS; TYPE-2 DIABETES-MELLITUS; BOVINE SERUM-ALBUMIN
• ISSN: 0022-2623; 1520-4804; 1520-4804
• DOI: 10.1021/acs.jmedchem.5b00726

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 ± 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.