Design and Characterization of a Selenium-Containing Inhibitor of Activated Thrombin-Activatable Fibrinolysis Inhibitor (TAFIa), a Zinc-Containing Metalloprotease

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• 作者：Nobuko Yoshimoto ; Tomoyuki Sasaki ; Katsuyoshi Sugimoto ; Hidemi Ishii ; Keiko Yamamoto
• 刊名：Journal of Medicinal Chemistry
• 出版年：2012
• 出版时间：September 13, 2012
• 年：2012
• 卷：55
• 期：17
• 页码：7696-7705
• 全文大小：350K
• 年卷期：v.55,no.17(September 13, 2012)
• ISSN：1520-4804

文摘

Available therapies for thromboembolic disorders include thrombolytics, anticoagulants, and antiplatelets, but these are associated with complications such as bleeding. To develop an alternative drug which is clinically safe, we focused on activated thrombin-activatable fibrinolysis inhibitor (TAFIa) as the target molecule. TAFIa is a zinc-containing carboxypeptidase that significantly inhibits fibrinolysis. Here we designed and synthesized selenium-containing compounds 5鈥?b>13 to discover novel TAFIa inhibitors having a superior zinc-coordinating group. Compounds 5鈥?b>13 significantly inhibited TAFIa activity (IC₅₀ 2.2 脳 10^鈥?2 M 鈥?2.6 脳 10^鈥? M). We found that selenol is a better functional group than thiol for coordinating to zinc at the active site of TAFIa. Furthermore, compound 12, which has an amino-chloro-pyridine ring, was found to be a potent and selective TAFIa inhibitor that lacks carboxypeptidase N inhibitory activity. Therefore, compound 12 is a promising candidate for the treatment of thromboembolic disorders. This is the first report of a selenium-containing inhibitor for TAFIa.