Discovery of diphenyloxazole and Ndelta-Z-ornithine derivatives as highly potent and selective human prostaglandin EP(4) receptor antagonists

Two novel classes of diphenyloxazole and Ndelta-Z-ornithine derivatives as highly potent and selective EP(4) antagonists have been discovered. The optimized diphenyloxzole 8 and Ndelta-Z-ornithine 11 effectively competed with [(3)H]PGE(2) binding to human recombinant EP(4), with K(i) values of 0.30...

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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:
Adjuvants, Immunologic - chemical synthesis
Adjuvants, Immunologic - pharmacokinetics
Adjuvants, Immunologic - pharmacology
Animals
B-Lymphocytes - drug effects
B-Lymphocytes - metabolism
Dinoprostone - pharmacology
Dogs
Humans
Immunoglobulin E - biosynthesis
In Vitro Techniques
Ornithine - analogs & derivatives
Ornithine - chemical synthesis
Ornithine - pharmacokinetics
Ornithine - pharmacology
Oxazoles - chemical synthesis
Oxazoles - pharmacokinetics
Oxazoles - pharmacology
Radioligand Assay
Rats
Receptors, Prostaglandin E - antagonists & inhibitors
Receptors, Prostaglandin E, EP4 Subtype
Stereoisomerism
Structure-Activity Relationship
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Summary:Two novel classes of diphenyloxazole and Ndelta-Z-ornithine derivatives as highly potent and selective EP(4) antagonists have been discovered. The optimized diphenyloxzole 8 and Ndelta-Z-ornithine 11 effectively competed with [(3)H]PGE(2) binding to human recombinant EP(4), 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 PGE(2)-promoted IgE synthesis.
ISSN:0022-2623