Structure-activity relationship studies leading to the identification of (2E)-3-[l-[(2,4-dichlorophenyl)methyl]-5-fluoro-3-methyl-lH-indol-7-yl]-N-[(4,5-dichloro-2-thienyl)sulfonyl]-2-propenamide (DG-041), a potent and selective prostanoid EP3 receptor antagonist, as a novel antiplatelet agent that does not prolong bleeding

J Med Chem. 2010 Jan 14;53(1):18-36. doi: 10.1021/jm9005912.

Abstract

The EP(3) receptor on the platelet mediates prostaglandin E(2) potentiation of thrombogenic coagonists including collagen and adenosine diphosphate (ADP). A pharmacophore driven approach led to the identification of diverse peri-substituted heterocycles as potent and selective EP(3) receptor antagonists. A simultaneous chemical optimization and druglike assessment of prioritized molecules converged on a lead compound 50 (DG-041) that displayed favorable in vitro and functional activities as an inhibitor of human platelet aggregation. This agent is currently in human clinical trials for the treatment of atherothrombosis.

MeSH terms

  • Acrylamides / chemical synthesis
  • Acrylamides / chemistry
  • Acrylamides / pharmacology*
  • Blood Coagulation / drug effects
  • Drug Discovery
  • Hemorrhage*
  • Humans
  • Ligands
  • Molecular Structure
  • Platelet Aggregation / drug effects*
  • Platelet Aggregation Inhibitors / chemical synthesis
  • Platelet Aggregation Inhibitors / chemistry
  • Platelet Aggregation Inhibitors / pharmacology*
  • Receptors, Prostaglandin E / antagonists & inhibitors*
  • Receptors, Prostaglandin E, EP3 Subtype
  • Stereoisomerism
  • Structure-Activity Relationship
  • Sulfones / chemical synthesis
  • Sulfones / chemistry
  • Sulfones / pharmacology*

Substances

  • 3-(1-((2,4-dichlorophenyl)methyl)-5-fluoro-3-methyl-1H-indol-7-yl)-N-((4,5-dichloro-2-thienyl)sulfonyl)-2-propenamide
  • Acrylamides
  • Ligands
  • PTGER3 protein, human
  • Platelet Aggregation Inhibitors
  • Receptors, Prostaglandin E
  • Receptors, Prostaglandin E, EP3 Subtype
  • Sulfones