GPR40 agonists for the treatment of type 2 diabetes mellitus: The biological characteristics and the chemical space

Bioorg Med Chem Lett. 2016 Dec 1;26(23):5603-5612. doi: 10.1016/j.bmcl.2016.10.074. Epub 2016 Oct 26.

Abstract

GPR40 belongs to the GPCR family and the activation of GPR40 has been shown to induce glucose-stimulated insulin secretion (GSIS) from pancreatic beta cells as well as incretin secretion from intestinal endocrine cells. Therefore, GPR40 has emerged as a viable and promising therapeutic target for type 2 diabetes mellitus (T2DM) without the risk of hypoglycemia. However, the termination of TAK-875 in phase III clinical trials for the hepatotoxicity issue threw doubt over the long-term safety of targeting GPR40. Herein, we summarized the newly disclosed biological characteristics and the druglikeness-based structural evolution of GPR40 agonists to advance the development of GPR40-based anti-diabetic drugs.

Keywords: Biased agonism; FFA1; GPR40; Glucose-stimulated insulin secretion; Type 2 diabetes.

Publication types

  • Review
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Benzofurans / chemistry
  • Benzofurans / pharmacology
  • Benzofurans / therapeutic use
  • Diabetes Mellitus, Type 2 / drug therapy*
  • Diabetes Mellitus, Type 2 / metabolism
  • Drug Discovery
  • Humans
  • Hypoglycemic Agents / chemistry*
  • Hypoglycemic Agents / pharmacology
  • Hypoglycemic Agents / therapeutic use*
  • Models, Molecular
  • Molecular Targeted Therapy
  • Receptors, G-Protein-Coupled / agonists*
  • Receptors, G-Protein-Coupled / metabolism
  • Sulfones / chemistry
  • Sulfones / pharmacology
  • Sulfones / therapeutic use

Substances

  • Benzofurans
  • FFAR1 protein, human
  • Hypoglycemic Agents
  • Receptors, G-Protein-Coupled
  • Sulfones
  • TAK-875