Hinkes Stefan, Wuttke André, Saupe Sebastian M, Ivanova Teodora, Wagner Sebastian, Knörlein Anna, Heine Andreas, Klebe Gerhard, Steinmetzer Torsten
Department of Pharmacy, Institute of Pharmaceutical Chemistry, Philipps University Marburg , Marbacher Weg 6, D-35032 Marburg, Germany.
J Med Chem. 2016 Jul 14;59(13):6370-86. doi: 10.1021/acs.jmedchem.6b00606. Epub 2016 Jun 17.
New macrocyclic plasmin inhibitors based on our previously optimized P2-P3 core segment have been developed. In the first series, the P4 residue was modified, whereas the 4-amidinobenzylamide in P1 position was maintained. The originally used P4 benzylsulfonyl residue could be replaced by various sulfonyl- or urethane-like protecting groups. In the second series, the P1 benzamidine was modified and a strong potency and excellent selectivity was retained by incorporation of p-xylenediamine. Several analogues inhibit plasmin in the subnanomolar range, and their potency against related trypsin-like serine proteases including trypsin itself could be further reduced. Selected derivatives have been tested in a plasma fibrinolysis assay and are more effective than the reference inhibitor aprotinin. The crystal structure of one inhibitor was determined in complex with trypsin. The binding mode reveals a sterical clash of the inhibitor's linker segment with the 99-hairpin loop of trypsin, which is absent in plasmin.
基于我们之前优化的P2 - P3核心片段，已开发出新型大环纤溶酶抑制剂。在第一个系列中，对P4残基进行了修饰，而P1位的4 - 脒基苄酰胺得以保留。最初使用的P4苄基磺酰基残基可被各种磺酰基或氨基甲酸酯类保护基团取代。在第二个系列中，对P1苯甲脒进行了修饰，通过引入对苯二胺保留了强效性和优异的选择性。几种类似物在亚纳摩尔范围内抑制纤溶酶，并且它们对包括胰蛋白酶本身在内的相关胰蛋白酶样丝氨酸蛋白酶的效力可进一步降低。所选衍生物已在血浆纤维蛋白溶解试验中进行了测试，且比参比抑制剂抑肽酶更有效。测定了一种抑制剂与胰蛋白酶复合物的晶体结构。该结合模式揭示了抑制剂的连接片段与胰蛋白酶的99 - 发夹环存在空间冲突，而在纤溶酶中不存在这种冲突。
