Design, synthesis, and structure-activity relationship of novel and effective apixaban derivatives as FXa inhibitors containing 1,2,4-triazole/pyrrole derivatives as P2 binding element

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• 作者：Yong Wang^a ; ^b ; Xiaoqing Sun^a ; ^b ; Di Yang^a ; ^b ; Zhuang Guo^a ; ^b ; Xuxu Fan^a ; ^b ; Minhua Nie^a ; ^b ; Feng Zhang^a ; ^b ; Yue Liu^a ; ^b ; Yue Li^a ; ^b ; Yulin Wang^c ; Ping Gong^a ; ^b ; Yajing Liu^a ; ^b ; ^{lyjpharm@126.com" class="auth_mail" title="E-mail the corresponding author}
• 关键词：FXa ; Anticoagulant activity ; Synthesis ; Structure&ndash ; activity relationships
• 刊名：Bioorganic & Medicinal Chemistry
• 出版年：2016
• 出版时间：1 November 2016
• 年：2016
• 卷：24
• 期：21
• 页码：5646-5661
• 全文大小：7998 K

文摘

Four series of novel and potent FXa inhibitors possessing the 1,2,4-triazole moiety and pyrrole moiety as P2 binding element and dihydroimidazole/tetrahydropyrimidine groups as P4 binding element were designed, synthesized, and evaluated for their anticoagulant activity in human and rabbit plasma in vitro. Most compounds showed moderate to excellent activity. Compounds 14a, 16, 18c, 26c, 35a, and 35b were further examined for their inhibition activity against human FXa in vitro and rat venous thrombosis in vivo. The most promising compound 14a, with an IC₅₀ (FXa) value of 0.15 μM and 99% inhibition rate, was identified for further evaluation as an FXa inhibitor.