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 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.
Hattori
Kouji
K
Medicinal Chemistry Research Laboratories, Fujisawa Pharmaceutical Co., Ltd., 2-1-6 Kashima, Yodogawa-ku, Osaka 532-8514, Japan. kouji_hattori@ po.fujisawa.co.jp
Tanaka
Akira
A
Fujii
Naoaki
N
Takasugi
Hisashi
H
Tenda
Yoshiyuki
Y
Tomita
Masayuki
M
Nakazato
Shoko
S
Nakano
Keiko
K
Kato
Yasuko
Y
Kono
Yutaka
Y
Murai
Hidetsugu
H
Sakane
Kazuo
K
D000276:Adjuvants, Immunologic / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D000818:Animals; D001402:B-Lymphocytes / Q000187:drug effects / Q000378:metabolism; D015232:Dinoprostone / Q000494:pharmacology; D004285:Dogs; D006801:Humans; D007073:Immunoglobulin E / Q000096:biosynthesis; D066298:In Vitro Techniques; D009952:Ornithine / Q000031:analogs & derivatives* / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D010080:Oxazoles / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D011869:Radioligand Assay; D051381:Rats; D018078:Receptors, Prostaglandin E / Q000037:antagonists & inhibitors*; D058309:Receptors, Prostaglandin E, EP4 Subtype; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
D000276:Adjuvants, Immunologic; D010080:Oxazoles; C545650:PTGER4 protein, human; D018078:Receptors, Prostaglandin E; D058309:Receptors, Prostaglandin E, EP4 Subtype; D007073:Immunoglobulin E; D009952:Ornithine; D015232:Dinoprostone