High Technology Research Center, Showa Pharmaceutical University, 3-3165 Higashi-Tamagawagakuen, Machida, Tokyo 194-8543, Japan.
J Med Chem. 2012 Sep 13;55(17):7696-705. doi: 10.1021/jm300735t. Epub 2012 Aug 27.
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 5-13 to discover novel TAFIa inhibitors having a superior zinc-coordinating group. Compounds 5-13 significantly inhibited TAFIa activity (IC(50) 2.2 × 10(-12) M - 2.6 × 10(-6) 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.
用于血栓栓塞性疾病的治疗方法包括溶栓药、抗凝剂和抗血小板药，但这些方法都与出血等并发症相关。为了开发一种临床安全的替代药物，我们将激活的凝血酶激活的纤溶抑制物（TAFIa）作为靶分子。TAFIa 是一种含锌的羧肽酶，能显著抑制纤维蛋白溶解。在这里，我们设计并合成了含硒化合物 5-13，以发现具有优越锌配位基团的新型 TAFIa 抑制剂。化合物 5-13 显著抑制 TAFIa 活性（IC50 为 2.2×10^(-12)M-2.6×10^(-6)M）。我们发现，硒醇比硫醇更适合在 TAFIa 的活性部位与锌配位。此外，具有氨基-氯-吡啶环的化合物 12 被发现是一种有效的、选择性的 TAFIa 抑制剂，缺乏羧肽酶 N 抑制活性。因此，化合物 12 是治疗血栓栓塞性疾病的有前途的候选药物。这是第一个关于 TAFIa 的含硒抑制剂的报告。
