3-Acrylamide-4-aryloxyindoles: synthesis, biological evaluation and metabolic stability of potent and selective EP3 receptor antagonists

A series of potent and selective EP(3) receptor antagonists are described. Utilizing a pharmacophore model developed for the EP(3) receptor, a series of 3,4-disubstituted indoles were found to be efficient ligands for this target. These compounds showed high selectivity over IP, FP and other EP rece...

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Bibliographic Details
Published in:Bioorganic & medicinal chemistry letters 2009-03, Vol.19 (5), p.1528-1531
Main Authors: Zhou, Nian, Zeller, Wayne, Zhang, Jun, Onua, Emmanuel, Kiselyov, Alex S, Ramirez, Jose, Palsdottir, Gudrún, Halldorsdottir, Gudrún, Andrésson, Thornorkell, Gurney, Mark E, Singh, Jasbir
Format: Article
Language:English
Subjects:
Acrylamides - chemical synthesis
Acrylamides - metabolism
Acrylamides - pharmacology
Animals
CHO Cells
Cricetinae
Cricetulus
Dogs
Dose-Response Relationship, Drug
Drug Evaluation, Preclinical - methods
Drug Stability
Haplorhini
Humans
Indoles - chemical synthesis
Indoles - metabolism
Indoles - pharmacology
Mice
Rats
Receptors, Prostaglandin E - antagonists & inhibitors
Receptors, Prostaglandin E - metabolism
Receptors, Prostaglandin E, EP3 Subtype
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Summary:A series of potent and selective EP(3) receptor antagonists are described. Utilizing a pharmacophore model developed for the EP(3) receptor, a series of 3,4-disubstituted indoles were found to be efficient ligands for this target. These compounds showed high selectivity over IP, FP and other EP receptors. An optimized molecule 7c featured a sound profile and potency in the functional rat and human platelet aggregation assays.
ISSN:0960-894X
1464-3405
DOI:10.1016/j.bmcl.2008.12.112