Discovery of a Potent Free Fatty Acid 1 Receptor Agonist with Low Lipophilicity, Low Polar Surface Area, and Robust in Vivo Efficacy

J Med Chem. 2016 Mar 24;59(6):2841-6. doi: 10.1021/acs.jmedchem.5b01962. Epub 2016 Mar 15.

Abstract

The free fatty acid receptor 1 (FFA1 or GPR40) is established as an interesting potential target for treatment of type 2 diabetes. However, to obtain optimal ligands, it may be necessary to limit both lipophilicity and polar surface area, translating to a need for small compounds. We here describe the identification of 24, a potent FFA1 agonist with low lipophilicity and very high ligand efficiency that exhibit robust glucose lowering effect.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Blood Glucose / metabolism
  • Diabetes Mellitus, Type 2 / drug therapy
  • Drug Discovery
  • Glucose Tolerance Test
  • Hypoglycemic Agents / chemical synthesis*
  • Hypoglycemic Agents / pharmacology*
  • Ligands
  • Lipids / chemistry
  • Mice
  • Mice, Inbred C57BL
  • Models, Molecular
  • Phenylpropionates / chemical synthesis*
  • Phenylpropionates / pharmacology*
  • Receptors, G-Protein-Coupled / agonists*
  • Structure-Activity Relationship

Substances

  • 3-(2-fluoro-4-(3-methylpent-3-en-1-yn-1-yl)phenyl)propanoic acid
  • Blood Glucose
  • Ffar1 protein, mouse
  • Hypoglycemic Agents
  • Ligands
  • Lipids
  • Phenylpropionates
  • Receptors, G-Protein-Coupled