Department of Pharmacy, Institute of Pharmaceutical Chemistry, Philipps University Marburg, Marbacher Weg 6, D-35032 Marburg, Germany.
J Med Chem. 2012 Feb 9;55(3):1171-80. doi: 10.1021/jm2011996. Epub 2012 Jan 25.
A new structure-based strategy for the design of potent and selective plasmin inhibitors was developed. These compounds could be prepared by cyclizations between the P3 and P2 amino acid residues of substrate-analogue inhibitors using metathesis or a copper-catalyzed azide alkyne cycloaddition in combination with standard peptide couplings. The most potent bis-triazole derivative 10 inhibits plasmin and plasma kallikrein with K(i) of 0.77 and 2.4 nM, respectively, whereas it has poor activity against the related trypsin-like serine proteases thrombin, factor Xa, or activated protein C. Modeling experiments revealed that inhibitor 10 adopts a compact and rigid structure that fits well into the relatively open active site of plasmin and plasma kallikrein, while it is rejected from sterically demanding residues present in loops of the other enzymes. These results from modeling confirm the selectivity profile found for inhibitor 10 in enzyme kinetic studies. Such compounds might be useful lead structures for the development of new antifibrinolytic drugs for use in cardiac surgery with cardiopulmonary bypass or organ transplantations to reduce bleeding complications.
我们开发了一种基于结构的新策略，用于设计强效且选择性的纤溶酶抑制剂。这些化合物可以通过使用复分解反应或铜催化的叠氮化物-炔烃环加成反应与标准肽偶联相结合，在底物类似物抑制剂的 P3 和 P2 氨基酸残基之间进行环化来制备。最有效的双三唑衍生物 10 对纤溶酶和血浆激肽释放酶的抑制常数（Ki）分别为 0.77 和 2.4 nM，而对相关的胰蛋白酶样丝氨酸蛋白酶凝血酶、因子 Xa 或活化蛋白 C 的活性较差。建模实验表明，抑制剂 10 采用紧凑且刚性的结构，非常适合纤溶酶和血浆激肽释放酶相对开放的活性位点，而在其他酶的环中存在的空间位阻要求高的残基处被排斥。这些来自建模的结果证实了在酶动力学研究中发现的抑制剂 10 的选择性特征。这些化合物可能是开发新的抗纤维蛋白溶解药物的有用先导结构，可用于体外循环心脏手术或器官移植，以减少出血并发症。
