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.
Jesper Lau  1 ,  Paw Bloch  1 ,  Lauge Schäffer  1 ,  Ingrid Pettersson  1 ,  Jane Spetzler  1 ,  Jacob Kofoed  1 ,  Kjeld Madsen  1 ,  Lotte Bjerre Knudsen  1 ,  James McGuire  1 ,  Dorte Bjerre Steensgaard  1 ,  Holger Martin Strauss  1 ,  Dorte X Gram  1 ,  Sanne Møller Knudsen  1 ,  Flemming Seier Nielsen  1 ,  Peter Thygesen  1 ,  Steffen Reedtz-Runge  1 ,  Thomas Kruse  1
Affiliations
  • 1. Global Research, Novo Nordisk A/S , Novo Nordisk Park, DK-2760 Måløv, Denmark.
PMID: 26308095 DOI: 10.1021/acs.jmedchem.5b00726
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.

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