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首页> 外文期刊>Journal of atherosclerosis and thrombosis. >Antiplatelet activity and structure-activity relationship study of Pyrazolopyridine Derivatives as potential series for treating thrombotic diseases
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Antiplatelet activity and structure-activity relationship study of Pyrazolopyridine Derivatives as potential series for treating thrombotic diseases

机译：吡唑并吡啶衍生物作为血栓性疾病治疗潜力系列的抗血小板活性及其构效关系研究

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Aim: Platelets plays a central role in hemostatic processes and consequently are similarly involved in pathological processes, such as arterial thrombosis and atherosclerosis. Herein we described the synthesis, antiplatelet profile and structure-activity relationship (SAR) of a new series of N' -substitutedphenylmethylene-1 H -pyrazolo[3,4- b ]pyridine-carbohydrazide derivatives (3a-3k). Methods: These compounds were synthesized in good yield and tested in platelet aggregation assays using collagen, ADP and arachidonic acid as agonists. We also performed a SAR studies using SPARTAN' 08 program, in silico ADMET screening and the Lipinski “ rule of five ” using Osiris Property Explorer and molinspiration on-line programs. Results: Interestingly, the new compounds were active against collagen and arachidonic acid (AA) with the two most actives compounds (3a and 3c - IC50=61 μM and 68 μM respectively) almost 5-fold more potent than aspirin (IC50=300 μM). These derivatives showed low theoretical toxicity risks in in silico ADMET screening and fulfilled the Lipinski rule of five, suggesting good oral biodisponibility. Conclusion: This work showed carbohydrazide group as potential for designing new antiplatelets. On that purpose, 3a and 3c may act as prototypes to generate more efficient and safe molecules for treating thrombotic diseases.
机译：目的：血小板在止血过程中起着核心作用，因此也类似地参与病理过程，例如动脉血栓形成和动脉粥样硬化。在这里，我们描述了一系列新的N'-取代的苯基亚甲基-1 H-吡唑并[3,4-b]吡啶-碳酰肼衍生物（3a-3k）的合成，抗血小板作用和结构-活性关系（SAR）。方法：这些化合物合成得率很高，并使用胶原蛋白，ADP和花生四烯酸作为激动剂在血小板凝集试验中进行了测试。我们还使用SPARTAN'08程序，计算机模拟ADMET筛选以及使用Osiris Property Explorer和molinspiration在线程序进行Lipinski“五个规则”进行了SAR研究。结果：有趣的是，新化合物对胶原蛋白和花生四烯酸（AA）具有活性，而两种活性最高的化合物（分别为3a和3c-IC 50 = 61μM和68μM）几乎增加了5倍。比阿司匹林更有效（IC 50 = 300μM）。这些衍生物在计算机模拟ADMET筛查中显示出较低的理论毒性风险，并满足Lipinski规则（五个规则），表明口服生物适应性良好。结论：这项工作表明卡巴肼组具有设计新抗血小板药的潜力。为此，3a和3c可以充当原型，以产生更有效，更安全的分子来治疗血栓性疾病。

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