Discovery of potent aryl-substituted 3-[(3-methylpyridine-2-carbonyl) amino]-2,4-dimethyl-benzoic acid EP4 antagonists with improved pharmacokinetic profile
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- 作者：Maria-Jesus Blanco ; blanco_maria@lilly.com" class="auth_mail" title="E-mail the corresponding author ; Tatiana Vetman ; Srinivasan Chandrasekhar ; Matthew J. Fisher ; Anita Harvey ; Mark Chambers ; Chaohua Lin ; Daniel Mudra ; Jennifer Oskins ; Xu-Shan Wang ; Xiao-Peng Yu ; Alan M. Warshawsky
- 关键词：EP4 receptor antagonist ; Structure&ndash ; activity relationship (SAR) ; Prostaglandin E2 ; Human whole blood (hWB) assay ; Inflammation ; Pain
- 刊名：Bioorganic & Medicinal Chemistry Letters
- 出版年：2016
- 出版时间：1 February 2016
- 年：2016
- 卷：26
- 期：3
- 页码：931-935
- 全文大小：641 K
文摘
Two new series of EP4 antagonists containing a 3-methylaryl-2-carbonyl core have been identified. One series has a 3-substituted-phenyl core, while the other one incorporates a 3-substituted pyridine. Both series led to compounds with potent activity in functional and human whole blood (hWB) assays. In the pyridine series, compound 7a was found to be a highly potent and selective EP4 antagonist, with suitable rat and dog pharmacokinetic profiles.