Discovery of potent and orally bioavailable indazole-based glucagon receptor antagonists for the treatment of type 2 diabetes

  • Bioorg Med Chem Lett. 2019 Oct 15;29(20):126668. doi: 10.1016/j.bmcl.2019.126668.
Guozhang Xu  1 ,  Michael D Gaul  2 ,  Fengbin Song  2 ,  Fuyong Du  3 ,  Yin Liang  3 ,  Renee L DesJarlais  2 ,  Karen DiLoreto  2 ,  Brian Shook  2 ,  Dennis Rentzeperis  3 ,  Rosie Santulli  3 ,  Annette Eckardt  3 ,  Keith Demarest  3
Affiliations
  • 1. Discovery Sciences, Janssen Research & Development, L.L.C., Welsh & McKean Roads, Spring House, PA 19477, USA. Electronic address: [email protected].
  • 2. Discovery Sciences, Janssen Research & Development, L.L.C., Welsh & McKean Roads, Spring House, PA 19477, USA.
  • 3. Cardiovascular & Metabolic Research, Janssen Research & Development, L.L.C., Welsh & McKean Roads, Spring House, PA 19477, USA.
PMID: 31519374 DOI: 10.1016/j.bmcl.2019.126668
Abstract

Type 2 diabetes mellitus (T2DM) is characterized by chronically elevated plasma glucose levels. The inhibition of glucagon-induced hepatic glucose output via antagonism of the Glucagon Receptor (GCGR) using a small-molecule antagonist is a promising mechanism for improving glycemic control in the diabetic state. The present work discloses the discovery of indazole-based β-alanine derivatives as potent GCGR antagonists through an efficient enantioselective synthesis and structure-activity relationship (SAR) exploration and optimization. Compounds within this class exhibited excellent pharmacokinetic properties in multiple preclinical species. In an acute dog glucagon challenge test, compound 13K significantly inhibited glucagon-mediated blood glucose increase when dosed orally at 10 mg/kg.

Keywords
Diabetes mellitus; Glucagon receptor antagonist; Indazole; Molecular modeling.
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