Structural optimization and structure-functional selectivity relationship studies of G protein-biased EP2 receptor agonists

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• 作者：Seiji Ogawa^a ; ^{s.ogawa@ono.co.jp" class="auth_mail" title="E-mail the corresponding author} ; Toshihide Watanabe^a ; Kazumi Moriyuki^b ; Yoshikazu Goto^b ; Shinsaku Yamane^c ; Akio Watanabe^a ; Kazuma Tsuboi^a ; Atsushi Kinoshita^a ; Takuya Okada^a ; Hiroyuki Takeda^a ; Kousuke Tani^c ; Toru Maruyama^a
• 关键词：Prostaglandin ; EP2 ; Agonist ; Biased ligand ; Structure&ndash ; functional selectivity relationship
• 刊名：Bioorganic & Medicinal Chemistry Letters
• 出版年：2016
• 出版时间：15 May 2016
• 年：2016
• 卷：26
• 期：10
• 页码：2446-2449
• 全文大小：1130 K

文摘

The modification of the novel G protein-biased EP2 agonist 1 has been investigated to improve its G protein activity and develop a better understanding of its structure–functional selectivity relationship (SFSR). The optimization of the substituents on the phenyl ring of 1, followed by the inversion of the hydroxyl group on the cyclopentane moiety led to compound 9, which showed a 100-fold increase in its G protein activity compared with 1 without any increase in β-arrestin recruitment. Furthermore, SFSR studies revealed that the combination of meta and para substituents on the phenyl moiety was crucial to the functional selectivity.