Synthesis and biological evaluation of phenoxyacetic acid derivatives as novel free fatty acid receptor 1 agonists

Bioorg Med Chem. 2015 Jan 1;23(1):132-40. doi: 10.1016/j.bmc.2014.11.016. Epub 2014 Nov 20.

Abstract

Free fatty acid receptor 1 (FFA1) is a new potential drug target for the treatment of type 2 diabetes because of its role in amplifying glucose-stimulated insulin secretion in pancreatic β-cell. In the present studies, we identified phenoxyacetic acid derivative (18b) as a potent FFA1 agonist (EC50=62.3 nM) based on the structure of phenylpropanoic acid derivative 4p. Moreover, compound 18b could significantly improve oral glucose tolerance in ICR mice and dose-dependently reduced glucose levels in type 2 diabetic C57BL/6 mice without observation of hypoglycemic side effect. Additionally, compound 18b exhibited acceptable PK profiles. In summary, compound 18b with ideal PK profiles exhibited good activity in vitro and in vivo, and might be a promising drug candidate for the treatment of diabetes mellitus.

Keywords: FFA1 agonist; Oral glucose tolerance test; Phenoxyacetic acid; β-oxidation.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acetates / chemical synthesis*
  • Acetates / chemistry
  • Acetates / pharmacokinetics
  • Acetates / pharmacology*
  • Animals
  • Diabetes Mellitus, Type 2 / drug therapy
  • Diabetes Mellitus, Type 2 / metabolism
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Inbred ICR
  • Models, Molecular
  • Rats
  • Receptors, G-Protein-Coupled / agonists*
  • Receptors, G-Protein-Coupled / chemistry
  • Structure-Activity Relationship

Substances

  • Acetates
  • FFAR1 protein, human
  • Receptors, G-Protein-Coupled
  • phenoxyacetic acid