Oral Presentation 12th Australian Peptide Conference 2017

Constrained and biased 11 amino acid glucagon-like peptide-1 receptor agonists (#64)

David A Griffith , David R Derksen 1 , David J Edmonds 2 , David P Fairlie 3 , Jean-Philippe Fortin , Timothy A Hill 3 , Huy N Hoang 3 , W Mei Kok 3 , Chris Limberakis 1 , Spiros Liras , Paula M Loria 1 , Vincent Mascitti 1 , Alan M Mathiowetz 1 , Justin M Mitchell 3 , David W Piotriwski 1 , David A Price , Kun Song , Robert V Stanton , Jacky Y Suen 3 , Jane M Withka 1
  1. Pfizer Inc, Groton, Connecticut, United States
  2. Pfizer Inc, Groton, Connecticut, United States
  3. Division of Chemistry and Structural Biology, Institute for Molecular Bioscience, University of Queensland, Brisbane, Queensland, Australia

Injectable peptide GLP-1 receptor (GLP-1R) agonists are highly effective anti-diabetic agents in clinical use. Constrained peptides with fewer polar side-chains were sought to facilitate oral bioavailability. Analysis of a potent 11 amino acid (11mer) peptide GLP-1R agonist by NMR and alanine scanning informed the design of conformationally constrained ligands that retained potent agonist activity. In addition, differences in the role of the N-terminal region of the 11mer peptide compared with GLP-1[7-36] were exposed. Further investigation of the N-terminal residue SAR led to the discovery of ligands with significant signaling bias between the cAMP and β-arrestin pathways.