Studies of Benzothiophene Template as Potent Factor IXa (FIXa) Inhibitors in Thrombosis

Citations Over TimeTop 15% of 2010 papers

Abstract

FIXa is a serine protease enzyme involved in the intrinsic pathway of the coagulation cascade. The upstream intervention of the coagulation cascade in selectively inhibiting FIXa would leave hemostasis intact via the extrinsic pathway, leading to an optimum combination of efficacy and safety with low incidence of bleeding. We have identified 2-amindinobenzothiophene template as a lead scaffold for FIXa inhibiton based on its homology with urokinase plasminogen activator (uPA). Subsequent SAR work on the template revealed a number of highly potent FIXa inhibitors, though with moderate selectivity against FXa. X-ray study with one of the analogues demonstrated active site binding interaction with the induced opening of the S1 beta pocket and a secondary binding at the S2-S4 sites, which is in direct contrast with the previous finding.

Related Papers

• → Studies of Benzothiophene Template as Potent Factor IXa (FIXa) Inhibitors in Thrombosis(2010)46 cited
• → Blood coagulation factor VIII: An overview(2003)39 cited
• → Mathematical Model of Serine Protease Inhibition in the Tissue Factor Pathway to Thrombin(1995)36 cited
• → Evaluation of Serine Protease Inhibitors as Potent FVIIa-sTF Inhibitors in the Blood Coagulation Cascade(2015)8 cited
• → Computational study of the putative active form of protein Z (PZa): Sequence design and structural modeling(2008)7 cited