Synthesis and evaluation of novel modified ¦Ã-lactam prostanoids as EP4 subtype-selective agonists

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• 作者：Tohru Kambe ; ^{kanbe@ono.co.jp} ; ^{t-kam@iris.dti.ne.jp} ; Toru Maruyama ; Toshihiko Nagase ; Seiji Ogawa ; Chiaki Minamoto ; Kiyoto Sakata ; Takayuki Maruyama ; Hisao Nakai ; Masaaki Toda
• 关键词：Prostaglandin ; EP4 receptor ; Agonist ; TNF-alpha
• 刊名：Bioorganic and Medicinal Chemistry
• 出版年：2012
• 出版时间：15 January, 2012
• 年：2012
• 卷：20
• 期：2
• 页码：702-713
• 全文大小：891 K

文摘

To identify chemically and metabolically stable subtype-selective EP4 agonists, design and synthesis of a series of modified ¦Ã-lactam prostanoids has been continued. Prostanoids bearing 2-oxo-1,3-oxazolidine, 2-oxo-1,3-thiazolidine and 5-thioxopyrrolidine as a surrogate for the ¦Ã-hydroxycyclopentanone without a troublesome 11-hydroxy group were identified as highly subtype-selective EP4 agonists. Among the tested, several representative compounds demonstrated in vivo efficacy after oral dosing in rats. Their pharmacokinetic and structure-activity relationship studies are presented.