Synthesis and evaluation of 纬-lactam analogs of PGE₂ as EP4 and EP2/EP4 agonists

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• 作者：Tohru Kambe ; ^{kanbe@ono.co.jp} ; ^{t-kam@iris.dti.ne.jp} ; Toru Maruyama ; Yoshihiko Nakai ; Hiroji Oida ; Takayuki Maruyama ; Nobutaka Abe ; Akio Nishiura ; Hisao Nakai ; Masaaki Toda
• 关键词：Prostaglandin ; EP4 receptor ; EP2 receptor ; Agonist
• 刊名：Bioorganic and Medicinal Chemistry
• 出版年：2012
• 期刊代码：9_09680896
• 类别：ch
• 出版时间：1 June, 2012
• 卷：20
• 期：11
• 页码：3502-3522
• 文件大小：2273 K

摘要

To identify topically effective EP4 agonists and EP2/EP4 dual agonists with excellent subtype selectivity, further optimization of the 16-phenyl 蠅-chain moiety of the 纬-lactam 5-thia prostaglandin E analog and the 2-mercaptothiazole-4-carboxylic acid analog were undertaken. Rat in vivo evaluation of these newly identified compounds as their poly (lactide-co-glycolide) microsphere formulation, from which sustained release of the test compound is possible, led us to discover compounds that showed efficacy in a rat bone fracture healing model after its topical administration without serious influence on blood pressure and heart rate. A structure-activity relationship study is also presented.