Peri-substituted hexahydro-indolones as novel, potent and selective human EP3 receptor antagonists

A series of peri-substituted [4.3.0] bicyclic non-aromatic heterocycles have been identified as potent and selective hEP(3) receptor antagonists. These molecules adopt a hair-pin conformation that overlaps with the endogenous ligand PGE(2) and fits into an internally generated EP(3) pharmacophore mo...

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Veröffentlicht in:	Bioorganic & medicinal chemistry letters 2009-02, Vol.19 (3), p.778-782
Hauptverfasser:	O'CONNELL, Matthew, ZELLER, Wayne, BURGESON, James, MISHRA, Rama K, RAMIREZ, Jose, KISELYOV, Alex S, ANDRESSON, Porkell, GURNEY, Mark E, SINGH, Jasbir
Format:	Artikel
Sprache:	eng
Schlagworte:	Alprostadil - analogs & derivatives Alprostadil - metabolism Animals Biological and medical sciences Chemistry, Pharmaceutical - methods CHO Cells Cricetinae Cricetulus Drug Design Humans Indoles - chemical synthesis Indoles - pharmacology Inhibitory Concentration 50 Ligands Magnetic Resonance Spectroscopy Medical sciences Miscellaneous Pharmacology. Drug treatments Prostaglandins - chemistry Receptors, Prostaglandin E - antagonists & inhibitors Receptors, Prostaglandin E - chemistry Receptors, Prostaglandin E, EP3 Subtype Sulfonamides - chemistry
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Zusammenfassung:	A series of peri-substituted [4.3.0] bicyclic non-aromatic heterocycles have been identified as potent and selective hEP(3) receptor antagonists. These molecules adopt a hair-pin conformation that overlaps with the endogenous ligand PGE(2) and fits into an internally generated EP(3) pharmacophore model. Optimized compounds show good metabolic stability and improved solubility over their corresponding bicyclic aromatic analogs.
ISSN:	0960-894X 1464-3405
DOI:	10.1016/j.bmcl.2008.12.027