Steinmetzer Torsten, Schweinitz Andrea, Künzel Sebastian, Wikström Peter, Hauptmann Jörg, Stürzebecher Jörg
Inst. of Biochemistry & Biophysics, Friedrich Schiller University, Jena, Germany.
J Enzyme Inhib Med Chem. 2002 Apr;17(2):241-9.
Several new analogs of the known thrombin inhibitor NAPAP were synthesized, in which the P2 glycine residue was substituted by natural and unnatural amino acids. The thrombin inhibitory potency was comparable to that of NAPAP. Several of the compounds had inhibition constants lower than 10 nM and a very high selectivity compared to trypsin, factor Xa and plasmin. In addition, analogs were prepared by alkylation of the N(alpha)-atom of the 4-amidinophenylalanine in P1 position, which showed a more than 10-fold lower thrombin inhibition. Furthermore, azaglycine was introduced instead of P2 glycine. For most of the inhibitors similar fast elimination rates were seen in rats after intravenous dosing, as found previously for NAPAP. Only some compounds, which contained a second basic group showed a slightly decreased cumulative biliary clearance.
合成了已知凝血酶抑制剂NAPAP的几种新类似物，其中P2位的甘氨酸残基被天然和非天然氨基酸取代。凝血酶抑制效力与NAPAP相当。几种化合物的抑制常数低于10 nM，与胰蛋白酶、因子Xa和纤溶酶相比具有非常高的选择性。此外，通过对P1位4-脒基苯丙氨酸的N(α)-原子进行烷基化制备了类似物，其凝血酶抑制作用降低了10倍以上。此外，引入氮杂甘氨酸取代P2位的甘氨酸。对于大多数抑制剂，静脉给药后在大鼠体内观察到与之前NAPAP相似的快速消除率。只有一些含有第二个碱性基团的化合物的累积胆汁清除率略有下降。
