2. Academic Validation
  3. 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

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.
Jasbir Singh 1,  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
Affiliations

Affiliation

  • 1 deCODE Chemistry, Inc., 2501 Davey Road, Woodridge, Illinois 60517, USA. JSingh@decode.com
PMID: 19957930 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.

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