3-(2-Aminocarbonylphenyl)propanoic acid analogs as potent and selective EP3 receptor antagonists. Part 3: Synthesis, metabolic stability, and biological evaluation of optically active analogs

被引：6

作者：

Asada, Masaki ^{[1
]}

Obitsu, Tetsuo ^{[1
]}

Kinoshita, Atsushi ^{[1
]}

Nagase, Toshihiko ^{[1
]}

Yoshida, Tadahiro ^{[1
]}

Yamaura, Yoshiyuki ^{[1
]}

Takizawa, Hiroya ^{[1
]}

Yoshikawa, Ken ^{[1
]}

Sato, Kazutoyo ^{[1
]}

Narita, Masami ^{[1
]}

Nakai, Hisao ^{[1
]}

Toda, Masaaki ^{[1
]}

Tobe, Yoshito ^{[2
]}

机构：

[1] Ono Pharmaceut Co Ltd, Minase Res Inst, Osaka 6188585, Japan

[2] Osaka Univ, Grad Sch Engn, Div Frontier Mat Sci, Osaka 5608531, Japan

来源：

BIOORGANIC & MEDICINAL CHEMISTRY | 2010年 / 18卷 / 09期

关键词：

Prostaglandin; EP3; receptor; Antagonist; Uterine contraction; MICE LACKING;

D O I：

10.1016/j.bmc.2010.03.028

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

A series of 3-(2-aminocarbonylphenyl)propanoic acid analogs possessing the (1R)-1-(3,5-dimethylphenyl)-3-methylbutylamine moiety on the carboxyamide side chain were synthesized and evaluated for their binding affinity for the EP1-4 receptors and their antagonist activity for the EP3 receptor. Rational drug design based on the structure of the metabolites in human liver microsomes led us to the discovery of another series of analogs. Several compounds were further evaluated for their in vivo efficacy in rats after oral administration and also for their pharmacokinetic profiles including in vitro stability in the liver microsomes. (c) 2010 Published by Elsevier Ltd.

引用

页码：3212 / 3223

页数：12

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