Design, synthesis, and structure-activity relationships of selective biphenyl antithrombotic tissue factor/factor...

The primary initiator for coagulation is the tissue factor (TF)-factor VIIa (FVIIa) cofactor-enzyme complex, TF-FVIIa. This complex leads to subsequent proteolytic activation of clotting factors. The TF-FVIIa complex plays a vital role in thrombosis-related diseases and is an attractive therapeutic target. Herein we report further optimization of our novel series of biphenyl antithrombotic agents as potent and selective TF-FVIIa inhibitors. Using a structure-guided drug design approach to explore the S1 and S' pockets of the FVIIa active site and building on compounds from earlier investigations of the S2 pocket, 41 new compounds were synthesized, including 24 compounds with TF-FVIIa IC₅₀ values of 30 nM or less. Structure-Activity Relationships (SARs) were evaluated in silico using the R-group decomposition function in StarDrop 7.0®. A sampling of the compounds was screened for selectivity against other human serine proteases. PT and aPTT assays were performed to provide insights of the inhibitor activity in the extrinsic and intrinsic coagulation pathways, respectively. Six compounds were chosen based on the coagulation assays to undergo PK studies. These six were poorly soluble and thus their oral PK profiles in rat models suffered. Future results will include efforts to improve bioavailability. This work represents the campaign that led to the discovery of BCX-3607 and its aims to improve upon it, identifying new, potent, and selective TF-FVIIa inhibitors.