| Abstract
| - Targeted 2-pyridones were selected as tissue Factor VIIa inhibitors and prepared from 2,6-dibromopyridine via a multistep synthesis. A variety of chemical transformations, includingregioselective nucleophilic addition, selective nitrogen alkylation, and a Suzuki coupling,afforded the targeted tissue Factor VIIa inhibitors. The pyridone core was selected as areplacement for the pyrazinone core of noncovalent tissue Factor VIIa inhibitors and designedsuch that their substitution pattern would occupy and interact with the S1, S2, and S3 pocketsof the tissue Factor VIIa enzyme. These compounds were tested in several serine proteaseenzyme assays involved in the coagulation cascade exhibiting modest activity on tissue FactorVIIa with excellent selectivity over thrombin and Factor Xa. Finally, an X-ray crystal structureof inhibitor 14a bound to tissue Factor VIIa was obtained and will be described.
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