title: Peri-substituted hexahydro-indolones as novel, potent and selective human EP3 receptor antagonists.
abstract: 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.
authors.affiliation: deCODE Chemistry, Inc., Medicinal Chemistry, 2501 Davey Road, Woodridge, IL 60517, USA.
authors.forename: Matthew
authors.initials: M
authors.lastname: O'Connell
authors.forename: Wayne
authors.initials: W
authors.lastname: Zeller
authors.forename: James
authors.initials: J
authors.lastname: Burgeson
authors.forename: Rama K
authors.initials: RK
authors.lastname: Mishra
authors.forename: Jose
authors.initials: J
authors.lastname: Ramirez
authors.forename: Alex S
authors.initials: AS
authors.lastname: Kiselyov
authors.forename: Thornorkell
authors.initials: T
authors.lastname: Andrésson
authors.forename: Mark E
authors.initials: ME
authors.lastname: Gurney
authors.forename: Jasbir
authors.initials: J
authors.lastname: Singh
mesh_terms: D000527:Alprostadil / Q000031:analogs & derivatives / Q000378:metabolism; D000818:Animals; D016466:CHO Cells; D002626:Chemistry, Pharmaceutical / Q000379:methods; D006224:Cricetinae; D003412:Cricetulus; D015195:Drug Design; D006801:Humans; D007211:Indoles / Q000138:chemical synthesis* / Q000494:pharmacology*; D020128:Inhibitory Concentration 50; D008024:Ligands; D009682:Magnetic Resonance Spectroscopy; D011453:Prostaglandins / Q000737:chemistry; D018078:Receptors, Prostaglandin E / Q000037:antagonists & inhibitors* / Q000737:chemistry; D058308:Receptors, Prostaglandin E, EP3 Subtype; D013449:Sulfonamides / Q000737:chemistry
chemical_list: D007211:Indoles; D008024:Ligands; C545647:PTGER3 protein, human; D011453:Prostaglandins; D018078:Receptors, Prostaglandin E; D058308:Receptors, Prostaglandin E, EP3 Subtype; D013449:Sulfonamides; C033246:prostaglandin E3; D000527:Alprostadil