Discovery of HWL-088: A highly potent FFA1/GPR40 agonist bearing a phenoxyacetic acid scaffold

Bioorg Chem. 2019 Nov:92:103209. doi: 10.1016/j.bioorg.2019.103209. Epub 2019 Aug 16.

Abstract

Based on a previously reported phenoxyacetic acid scaffold, compound 7 (HWL-088) has been identified as a superior free fatty acid receptor 1 (FFA1) agonist by comprehensive structure-activity relationship study. Our results indicated that the introduction of ortho-fluoro greatly increased the activity of phenoxyacetic acid series, and the unique structure-activity relationship in biphenyl moiety is different from previously reported FFA1 agonists. Moreover, the modeling study was also performed to better understand the binding mode of present series. Compound 7 significantly improved glucose tolerance both in normal and diabetic models, and even exerted greater potential on glucose control than that of TAK-875. These findings provided a novel candidate HWL-088, which is currently in preclinical study to evaluate its potential for the treatment of diabetes.

Keywords: Diabetes; FFA1; GPR40; Hyperglycemia; Phenoxyacetic acid.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acetates / chemistry
  • Acetates / pharmacology*
  • Animals
  • CHO Cells
  • Cricetulus
  • Diabetes Mellitus, Experimental / chemically induced
  • Diabetes Mellitus, Experimental / drug therapy*
  • Diabetes Mellitus, Experimental / metabolism
  • Diabetes Mellitus, Type 2 / chemically induced
  • Diabetes Mellitus, Type 2 / drug therapy*
  • Disease Models, Animal
  • Dose-Response Relationship, Drug
  • Drug Discovery*
  • Glucose Tolerance Test
  • Hypoglycemic Agents / chemical synthesis
  • Hypoglycemic Agents / chemistry
  • Hypoglycemic Agents / pharmacology*
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Inbred ICR
  • Molecular Docking Simulation
  • Molecular Structure
  • Receptors, G-Protein-Coupled / agonists*
  • Receptors, G-Protein-Coupled / metabolism
  • Structure-Activity Relationship

Substances

  • Acetates
  • Ffar1 protein, mouse
  • Hypoglycemic Agents
  • Receptors, G-Protein-Coupled
  • phenoxyacetic acid