Discovery of a Highly Potent, Selective, and Orally Bioavailable Macrocyclic Inhibitor of Blood Coagulation Factor VIIa–Tissue Factor Complex

Inhibitors of the tissue factor (TF)/factor
VIIa complex (TF-FVIIa)
are promising novel anticoagulants which show excellent efficacy and
minimal bleeding in preclinical models. Starting with an aminoisoquinoline
P1-based macrocyclic inhibitor, optimization of the P′ groups
led to a series of highly potent and selective TF-FVIIa inhibitors
which displayed poor permeability. Fluorination of the aminoisoquinoline
reduced the basicity of the P1 group and significantly improved permeability.
The resulting lead compound was highly potent, selective, and achieved
good pharmacokinetics in dogs with oral dosing. Moreover, it demonstrated
robust antithrombotic activity in a rabbit model of arterial thrombosis.