Wienand A, Ehrhardt C, Metternich R, Tapparelli C
Novartis Pharma AG, Research, Basel, Switzerland.
Bioorg Med Chem. 1999 Jul;7(7):1295-307. doi: 10.1016/s0968-0896(99)00069-3.
Based on the structural comparison of the S-1 pocket in different trypsin-like serine proteases, a series of Boc-D-trimethylsilylalanine-proline-boro-X pinanediol derivatives, with boro-X being different amino boronic acids, have been synthesised as inhibitors of thrombin. The influence of hydrogen donor/acceptor properties of different residues in the P-1 side chain of these inhibitors on the selectivity profile has been investigated. This study confirmed the structure-based working hypothesis: The hydrophobic/hydrophilic character of amino acid residues 190 and 213 in the neighbourhood of Asp 189 in the S-1 pocket of thrombin (Ala/Val), trypsin (Ser/Val) and plasmin (Ser/Thr) define the specificity for the interaction with different P-1 residues of the inhibitors. Many of the synthesised compounds demonstrate potent antithrombin activity with Boc-D-trimethylsilylalanine-proline-boro-methoxypropylglycine++ + pinanediol (9) being the most selective thrombin inhibitor of this series.
基于对不同胰蛋白酶样丝氨酸蛋白酶中S-1口袋的结构比较，合成了一系列Boc-D-三甲基硅烷基丙氨酸-脯氨酸-硼-X蒎烷二醇衍生物，其中硼-X为不同的氨基硼酸，作为凝血酶抑制剂。研究了这些抑制剂P-1侧链中不同残基的氢供体/受体性质对选择性的影响。本研究证实了基于结构的工作假设：凝血酶（丙氨酸/缬氨酸）、胰蛋白酶（丝氨酸/缬氨酸）和纤溶酶（丝氨酸/苏氨酸）S-1口袋中靠近天冬氨酸189的氨基酸残基190和213的疏水/亲水特性决定了与抑制剂不同P-1残基相互作用的特异性。许多合成化合物表现出强大的抗凝血酶活性，其中Boc-D-三甲基硅烷基丙氨酸-脯氨酸-硼-甲氧基丙基甘氨酸++ +蒎烷二醇（9）是该系列中最具选择性的凝血酶抑制剂。
