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

• Published in: Journal of medicinal chemistry Vol. 53; no. 1; pp. 18 - 36
• Main Authors: Singh, Jasbir, Zeller, Wayne, Zhou, Nian, Hategan, Georgeta, Mishra, Rama K, Polozov, Alex, Yu, Peng, Onua, Emmanuel, Zhang, Jun, Ramírez, José L, Sigthorsson, Gudmundur, Thorsteinnsdottir, Margret, Kiselyov, Alex. S, Zembower, David E, Andrésson, Thorkell, Gurney, Mark E
• Format: Journal Article
• Language: English
• Published: United States American Chemical Society 14.01.2010
• Subjects: 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
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm9005912

The EP3 receptor on the platelet mediates prostaglandin E2 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.