Discovery of novel prostaglandin analogs as potent and selective EP2/EP4 dual agonists

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• 作者：Tohru Kambe ; ^{kanbe@ono.co.jp} ; ^{t-kam@iris.dti.ne.jp} ; Toru Maruyama ; Yoshihiko Nakai ; Hideyuki Yoshida ; Hiroji Oida ; Takayuki Maruyama ; Nobutaka Abe ; Akio Nishiura ; Hisao Nakai ; Masaaki Toda
• 关键词：Prostaglandin ; EP2 receptor ; EP4 receptor
• 刊名：Bioorganic and Medicinal Chemistry
• 出版年：2012
• 出版时间：1 April, 2012
• 年：2012
• 卷：20
• 期：7
• 页码：2235-2251
• 全文大小：1260 K

文摘

To identify potent EP2/EP4 dual agonists with excellent subtype selectivity, a series of ¦Ã-lactam prostaglandin E analogs bearing a 16-phenyl ¦Ø-chain were synthesized and evaluated. Structural hybridization of 1 and 2, followed by more detailed chemical modification of the benzoic acid moiety, led us to the discovery of a 2-mercaptothiazole-4-carboxylic acid analog 3 as the optimal compound in the series. An isomer of this compound, the 2-mercaptothiazole-5-carboxylic acid analog 13, showed 34-fold and 13-fold less potent EP2 and EP4 receptor affinities, respectively. Structure activity relationship data from an in vitro mouse receptor binding assay are presented. Continued evaluation in an in vivo rat model of another 2-mercaptothiazole-4-carboxylic acid analog 17, optimized for sustained compound release from PLGA microspheres, demonstrated its effectiveness in a rat bone fracture-healing model following topical administration.