一种通过单硫酸化疏水支架实现变构凝血酶抑制的简单通用方法。

A simple, general approach of allosteric coagulation enzyme inhibition through monosulfated hydrophobic scaffolds.

作者信息

Sidhu Preetpal Singh, Zhou Qibing, Desai Umesh R

机构信息

Department of Medicinal Chemistry, Virginia Commonwealth University, Richmond, VA 23219, United States; Institute for Structural Biology and Drug Discovery, Virginia Commonwealth University, Richmond, VA 23219, United States.

Institute for Materia Medica, College of Life Science and Technology, Huazhong University of Science and Technology, Wuhan, Hunan 430074, PR China.

出版信息

Bioorg Med Chem Lett. 2014 Dec 15;24(24):5716-5720. doi: 10.1016/j.bmcl.2014.10.059. Epub 2014 Oct 23.

DOI:10.1016/j.bmcl.2014.10.059

PMID:25453807

Abstract

Allosteric inhibition of coagulation enzymes offers the advantage of controlled inhibition. In this study, a small library of mono sulfated indole and benzothiazole based molecules was synthesized and screened against the panel of coagulation proteases. The results reveal that selected molecules inhibit the thrombin, factor Xa and factor XIa with moderate potency. Compound 6a was found to have an allosteric mode of inhibition against thrombin. Plasma clotting assays suggest that selected inhibitors 14b, 14c and 14d prolong both prothrombin and activated partial thromboplastin time. Overall, this work presents the newer class of allosteric inhibitors of thrombin and factor XIa with improved aqueous solubility profile.

摘要

凝血酶的变构抑制具有可控抑制的优势。在本研究中，合成了一个基于单硫酸化吲哚和苯并噻唑的小分子文库，并针对一系列凝血蛋白酶进行筛选。结果表明，所选分子对凝血酶、因子Xa和因子XIa具有中等强度的抑制作用。发现化合物6a对凝血酶具有变构抑制模式。血浆凝血试验表明，所选抑制剂14b、14c和14d可延长凝血酶原时间和活化部分凝血活酶时间。总体而言，这项工作展示了具有改善水溶性特征的新型凝血酶和因子XIa变构抑制剂。