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

Sidhu PS1, Zhou Q2, Desai UR3. A simple, general approach of allosteric coagulation enzyme inhibition through monosulfated hydrophobic scaffolds. Bioorg Med Chem Lett. 2014 Dec 15;24(24):5716-20. 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.

KEYWORDS: Anticoagulation; Factor XIa; Sulfation; Thrombin