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

J Med Chem. 2015 Sep 24;58(18):7370-80. doi: 10.1021/acs.jmedchem.5b00726. Epub 2015 Sep 11.

Abstract

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 (Aib(8), Arg(34)) 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.

MeSH terms

  • Administration, Intravenous
  • Animals
  • Cell Line
  • 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
  • Liraglutide / pharmacology
  • Male
  • Mice, Obese
  • Models, Molecular
  • Rats, Sprague-Dawley
  • Structure-Activity Relationship
  • Swine
  • Swine, Miniature

Substances

  • Glucagon-Like Peptide-1 Receptor
  • semaglutide
  • Glucagon-Like Peptides
  • Liraglutide
  • Glucagon-Like Peptide 1