Discovery of novel pyrrole-based scaffold as potent and orally bioavailable free fatty acid receptor 1 agonists for the treatment of type 2 diabetes

Bioorg Med Chem. 2016 May 1;24(9):1981-7. doi: 10.1016/j.bmc.2016.03.014. Epub 2016 Mar 7.

Abstract

The free fatty acid receptor 1 (FFA1) has gained significant interest as a novel antidiabetic target. Most of FFA1 agonists reported in the literature bearing a common biphenyl scaffold, which was crucial for toxicity verified by the researchers of Daiichi Sankyo. Herein, we describe the systematic exploration of non-biphenyl scaffold and further chemical modification of the optimal pyrrole scaffold. All of these efforts led to the identification of compound 11 as a potent and orally bioavailable FFA1 agonist without the risk of hypoglycemia. Further molecular modeling studies promoted the understanding of ligand-binding pocket and might help to design more promising FFA1 agonists.

Keywords: FFA1 agonist; GPR40; Ligand efficiency; Pyrrole; Type 2 diabetes.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Administration, Oral
  • Animals
  • Biological Availability
  • Diabetes Mellitus, Type 2 / drug therapy*
  • Disease Models, Animal
  • Drug Discovery
  • Glucose Tolerance Test
  • Male
  • Mice
  • Mice, Inbred ICR
  • Molecular Docking Simulation
  • Pyrroles / chemistry*
  • Receptors, G-Protein-Coupled / agonists*
  • Structure-Activity Relationship

Substances

  • Ffar1 protein, mouse
  • Pyrroles
  • Receptors, G-Protein-Coupled