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
详细信息 查看全文
- 作者：Masaki Asada ; Tetsuo Obitsu ; Atsushi Kinoshita ; Toshihiko Nagase ; Tadahiro Yoshida ; Yoshiyuki Yamaura ; Hiroya Takizawa ; Ken Yoshikawa ; Kazutoyo Sato ; Masami Narita ; Hisao Nakai ; Masaaki Toda ; Yoshito
- 关键词：Prostaglandin ; EP3 receptor ; Antagonist ; Uterine contraction
- 刊名：Bioorganic and Medicinal Chemistry
- 出版年：2010
- 出版时间：1 May 2010
- 年：2010
- 卷：18
- 期：9
- 页码：3212-3223
- 全文大小：568 K
文摘
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.