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 model. Optimized compounds show good metabolic stability and improved solubility over their corresponding bicyclic aromatic analogs.
O'Connell
Matthew
M
deCODE Chemistry, Inc., Medicinal Chemistry, 2501 Davey Road, Woodridge, IL 60517, USA.
Zeller
Wayne
W
Burgeson
James
J
Mishra
Rama K
RK
Ramirez
Jose
J
Kiselyov
Alex S
AS
Andrésson
Thornorkell
T
Gurney
Mark E
ME
Singh
Jasbir
J
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
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