Heterocyclic 1,7-disubstituted indole sulfonamides are potent and selective human EP3 receptor antagonists

We have developed a pharmacophore model for the EP(3) receptor antagonists based on its endogenous ligand PGE(2). This ligand-based design yielded a series of novel peri-substituted [4.3.0] bicyclic aromatics featuring 1-alklyaryl 7-heterocyclic sulfonamide substituents. The synthesized molecules ar...

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Veröffentlicht in:	Bioorganic & medicinal chemistry letters 2009-12, Vol.19 (23), p.6797-6800
Hauptverfasser:	HATEGAN, Georgeta, POLOZOV, Alexandre M, SINGH, Jasbir, ZELLER, Wayne, HUA CAO, MISHRA, Rama K, KISELYOV, Alex S, RAMIREZ, Jose, HALLDORSDOTTIR, Guðrún, ANDRESSON, Porkell, GURNEY, Mark E
Format:	Artikel
Sprache:	eng
Schlagworte:	Biological and medical sciences Blood. Blood coagulation. Reticuloendothelial system Crystallography, X-Ray Dose-Response Relationship, Drug Drug Design Heterocyclic Compounds - chemical synthesis Heterocyclic Compounds - chemistry Heterocyclic Compounds - pharmacology Humans Indoles - chemical synthesis Indoles - chemistry Indoles - pharmacology Medical sciences Models, Molecular Molecular Structure Pharmacology. Drug treatments Receptors, Prostaglandin E - antagonists & inhibitors Receptors, Prostaglandin E, EP3 Subtype Stereoisomerism Structure-Activity Relationship Sulfonamides - chemical synthesis Sulfonamides - chemistry Sulfonamides - pharmacology
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Zusammenfassung:	We have developed a pharmacophore model for the EP(3) receptor antagonists based on its endogenous ligand PGE(2). This ligand-based design yielded a series of novel peri-substituted [4.3.0] bicyclic aromatics featuring 1-alklyaryl 7-heterocyclic sulfonamide substituents. The synthesized molecules are potent antagonists of human EP(3) receptor in vitro and show inhibition of rat platelets aggregation. Optimized derivatives display high selectivity over IP, FP, and other EP receptor panels.
ISSN:	0960-894X 1464-3405
DOI:	10.1016/j.bmcl.2009.09.084