Discovery of Diphenyloxazole and Nδ-Z-Ornithine Derivatives as Highly Potent and Selective Human Prostaglandin EP4 Receptor Antagonists

Two novel classes of diphenyloxazole and Nδ-Z-ornithine derivatives as highly potent and selective EP4 antagonists have been discovered. The optimized diphenyloxzole 8 and Nδ-Z-ornithine 11 effectively competed with [3H]PGE2 binding to human recombinant EP4, with K i values of 0.30 nM and 0.91 nM, r...

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Bibliographic Details
Published in:Journal of medicinal chemistry 2005-05, Vol.48 (9), p.3103-3106
Main Authors: Hattori, Kouji, Tanaka, Akira, Fujii, Naoaki, Takasugi, Hisashi, Tenda, Yoshiyuki, Tomita, Masayuki, Nakazato, Shoko, Nakano, Keiko, Kato, Yasuko, Kono, Yutaka, Murai, Hidetsugu, Sakane, Kazuo
Format: Article
Language:English
Subjects:
Biological and medical sciences
Medical sciences
Miscellaneous
Pharmacology. Drug treatments
Online Access:Get full text
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Summary:Two novel classes of diphenyloxazole and Nδ-Z-ornithine derivatives as highly potent and selective EP4 antagonists have been discovered. The optimized diphenyloxzole 8 and Nδ-Z-ornithine 11 effectively competed with [3H]PGE2 binding to human recombinant EP4, with K i values of 0.30 nM and 0.91 nM, respectively, and were selective for all members of the human prostanoid receptor family. 8 was shown to exhibit good pharmacokinetic properties in rats and dogs and potent inhibitory activity toward in vitro PGE2-promoted IgE synthesis.
ISSN:0022-2623
1520-4804
DOI:10.1021/jm050085k