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

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

Affiliations

  • 1 Discovery Sciences, Janssen Research & Development, L.L.C., Welsh & McKean Roads, Spring House, PA 19477, USA. Electronic address: gxu4@its.jnj.com.
  • 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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