Institute of Pharmaceutical Chemistry, Philipps University, Marbacher Weg 6, D-35032, Marburg, Germany.
CrystalsFirst GmbH, Marbacher Weg 6, D-35032, Marburg, Germany.
Eur J Med Chem. 2022 Aug 5;238:114437. doi: 10.1016/j.ejmech.2022.114437. Epub 2022 May 12.
A rational structure-based approach was employed to develop novel 3-amidinophenylalanine-derived matriptase inhibitors with improved selectivity against thrombin and factor Xa. Of all 23 new derivatives, several monobasic inhibitors exhibit high matriptase affinities and strong selectivity against thrombin. Some inhibitors also possess selectivity against factor Xa, although less pronounced as found for thrombin. A crystal structure of a selective monobasic matriptase inhibitor in complex with matriptase and three crystal structures of related compounds in trypsin and thrombin have been determined. The structures offer an explanation for the different selectivity profiles of these inhibitors and contribute to a more detailed understanding of the observed structure-activity relationship. Selected compounds were tested in vitro against a matriptase-dependent H9N2 influenza virus strain and demonstrated a concentration-dependent inhibition of virus replication in MDCK(II) cells.
采用合理的基于结构的方法，开发了新型的 3-氨甲酰基苯丙氨酸衍生的组织蛋白酶抑制剂，对凝血酶和因子 Xa 的选择性得到改善。在所有 23 种新衍生物中，几种单碱抑制剂表现出对组织蛋白酶的高亲和力和对凝血酶的强选择性。一些抑制剂对因子 Xa 也具有选择性，尽管不如对凝血酶那么明显。已确定了一种选择性单碱组织蛋白酶抑制剂与组织蛋白酶以及三种相关化合物在胰蛋白酶和凝血酶中的复合物的晶体结构。这些结构为这些抑制剂的不同选择性特征提供了解释，并有助于更详细地了解观察到的结构-活性关系。选择的化合物在体外针对依赖于组织蛋白酶的 H9N2 流感病毒株进行了测试，并在 MDCK(II)细胞中显示出对病毒复制的浓度依赖性抑制。
