具有在回肠中蓄积倾向和反应性的口服活性非甾体类法尼醇X受体（FXR）拮抗剂的发现。
Discovery of Orally Active and Nonsteroidal Farnesoid X Receptor (FXR) Antagonist with Propensity for Accumulation and Responsiveness in Ileum.
作者信息
Teno Naoki, Iguchi Yusuke, Oda Keisuke, Yamashita Yukiko, Masuda Arisa, Fujimori Ko, Une Mizuho, Gohda Keigo
机构信息
Graduate School of Pharmaceutical Sciences, Faculty of Clinical Nutrition, and Faculty of Pharmaceutical Sciences, Hiroshima International University, 5-1-1 Hirokoshingai, Kure, Hiroshima 737-0112, Japan.
Department of Pathobiochemistry, Osaka University of Pharmaceutical Sciences, 4-20-1 Nasahara, Takatsuki, Osaka 569-1094, Japan.
出版信息
ACS Med Chem Lett. 2021 Feb 24;12(3):420-425. doi: 10.1021/acsmedchemlett.0c00640. eCollection 2021 Mar 11.
Abstract
We describe the discovery of analog (FLG249), which is an orally active and nonsteroidal farnesoid X receptor (FXR) antagonist in mice with unique profiles, such as a propensity for ileum distribution and the significant control in the expression level of three FXR target genes in mouse ileum. Key design features incorporated in were the introduction of metabolically stable groups in potent and metabolically labile antagonist . Our pursuit ultimately identified FXR antagonist , which has enabled its assessment in a drug discovery program.
摘要
我们描述了类似物（FLG249）的发现，它是一种口服活性非甾体类法尼醇X受体（FXR）拮抗剂，在小鼠中具有独特的特性，比如倾向于在回肠分布，并且能显著控制小鼠回肠中三个FXR靶基因的表达水平。纳入FLG249的关键设计特征是在强效且代谢不稳定的拮抗剂中引入代谢稳定基团。我们的研究最终确定了FXR拮抗剂FLG249，这使其能够在药物发现计划中进行评估。
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