Identification of a novel conformationally constrained glucagon receptor antagonist

  • Bioorg Med Chem Lett. 2014 Feb 1;24(3):839-44. doi: 10.1016/j.bmcl.2013.12.090.
Esther C Y Lee  1 ,  Meihua Tu  2 ,  Benjamin D Stevens  2 ,  Jianwei Bian  3 ,  Gary Aspnes  3 ,  Christian Perreault  3 ,  Matthew F Sammons  2 ,  Stephen W Wright  3 ,  John Litchfield  2 ,  Amit S Kalgutkar  2 ,  Raman Sharma  3 ,  Mary T Didiuk  3 ,  David C Ebner  2 ,  Kevin J Filipski  2 ,  Janice Brown  3 ,  Karen Atkinson  3 ,  Jeffrey A Pfefferkorn  2 ,  Angel Guzman-Perez  3
Affiliations
  • 1. Pfizer Worldwide Research & Development, 620 Memorial Drive, Cambridge, MA 02139, United States. Electronic address: [email protected].
  • 2. Pfizer Worldwide Research & Development, 620 Memorial Drive, Cambridge, MA 02139, United States.
  • 3. Pfizer Worldwide Research & Development, Eastern Point Rd., Groton, CT 06340, United States.
PMID: 24418771 DOI: 10.1016/j.bmcl.2013.12.090
Abstract

Identification of orally active, small molecule antagonists of the Glucagon Receptor represents a novel treatment paradigm for the management of type 2 diabetes mellitus. The present work discloses novel Glucagon Receptor antagonists, identified via conformational constraint of current existing literature antagonists. Optimization of lipophilic ligand efficiency (LLE or LipE) culminated in enantiomers (+)-trans-26 and (-)-trans-27 which exhibit good physicochemical and in vitro drug metabolism profiles. In vivo, significant pharmacokinetic differences were noted with the two enantiomers, which were primarily driven through differences in clearance rates. Enantioselective oxidation by Cytochrome P450 was ruled out as a causative factor for pharmacokinetic differences.

Keywords
Diabetes mellitus; Glucagon receptor antagonist; Metabolite; Physicochemical properties.
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