Marinko Petra, Krbavcic Ales, Mlinsek Gregor, Solmajer Tomaz, Bakija Alenka Trampus, Stegnar Mojca, Stojan Jure, Kikelj Danijel
Faculty of Pharmacy, University of Ljubljana, Askerceva 7, 1000 Ljubljana, Slovenia.
Eur J Med Chem. 2004 Mar;39(3):257-65. doi: 10.1016/j.ejmech.2003.12.006.
The design, synthesis and biological activity of a series of novel non-covalent D-Phe-Pro-Arg motif-based thrombin inhibitors incorporating 4,5,6,7-tetrahydrobenzothiazol-2-amine as a novel arginine surrogate are described. Compound 9, the most potent in the series of thrombin inhibitors, exhibited an in vitro K(i) of 128 nM and 342-fold selectivity against trypsin. The binding mode of this novel class of thrombin inhibitors in the enzyme active site, based on the X-ray crystal structure of compound 9 co-crystallized with human alpha-thrombin, is discussed.
描述了一系列新型基于非共价D-苯丙氨酸-脯氨酸-精氨酸基序的凝血酶抑制剂的设计、合成及生物活性，这些抑制剂将4,5,6,7-四氢苯并噻唑-2-胺作为新型精氨酸替代物。化合物9是该系列凝血酶抑制剂中活性最强的，其体外抑制常数（K(i)）为128 nM，对胰蛋白酶的选择性为342倍。基于化合物9与人α-凝血酶共结晶的X射线晶体结构，讨论了这类新型凝血酶抑制剂在酶活性位点的结合模式。
