Discovery of LY3325656: A GPR142 agonist suitable for clinical testing in human

Bioorg Med Chem Lett. 2020 Mar 1;30(5):126857. doi: 10.1016/j.bmcl.2019.126857. Epub 2019 Dec 27.

Abstract

The discovery and optimization of a novel series of GPR142 agonists are described. These led to the identification of compound 21 (LY3325656), which demonstrated anti-diabetic benefits in pre-clinical studies and ADME/PK properties suitable for human dosing. Compound 21 is the first GPR142 agonist molecule advancing to phase 1 clinic trials for the treatment of Type 2 diabetes.

Keywords: GPR142 agonist; Glucose-dependent insulin secretion; Metabolism; Type 2 diabetes.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Benzamides / chemical synthesis
  • Benzamides / pharmacokinetics
  • Benzamides / therapeutic use*
  • Diabetes Mellitus, Experimental / drug therapy*
  • Dogs
  • Drug Discovery
  • Drug Evaluation, Preclinical
  • Gene Knockout Techniques
  • Humans
  • Hypoglycemic Agents / chemical synthesis
  • Hypoglycemic Agents / pharmacokinetics
  • Hypoglycemic Agents / therapeutic use*
  • Mice, Knockout
  • Molecular Structure
  • Rats
  • Receptors, G-Protein-Coupled / agonists*
  • Receptors, G-Protein-Coupled / genetics
  • Structure-Activity Relationship
  • Triazoles / chemical synthesis
  • Triazoles / pharmacokinetics
  • Triazoles / therapeutic use*

Substances

  • Benzamides
  • GPR142 protein, human
  • GPR142 protein, mouse
  • Hypoglycemic Agents
  • Receptors, G-Protein-Coupled
  • Triazoles