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

Jasbir Singh*, Wayne Zeller, Nian Zhou, Georgeta Hategan, Rama K. Mishra, Alex Polozov, Peng Yu, Emmanuel Onua, Jun Zhang, José L. Ramírez, Gudmundur Sigthorsson, Margret Thorsteinnsdottir, Alex S. Kiselyov, David E. Zembower, Thorkell Andrésson, Mark E. Gurney

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

33 Scopus citations

Abstract

The EP3 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 EP3 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.

Original languageEnglish (US)
Pages (from-to)18-36
Number of pages19
JournalJournal of Medicinal Chemistry
Volume53
Issue number1
DOIs
StatePublished - Jan 28 2010

ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery

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