Design, Synthesis and Characterization of a Novel Class of Coumarin-Based Inhibitors of Inducible Nitric Oxide Synthase

Abstract Inducible nitric oxide synthase (iNOS) has been implicated in various central and peripheral pathophysiological diseases. Our high throughput screening initially identified a weak inhibitor of iNOS, thiocoumarin 13 . From this lead, a number of potent derivatives were prepared that demonstrate favorable potency, selectivity and kinetics. Compound 30 has an IC 50 of 60 nM for mouse iNOS and 185-fold and 9-fold selectivity for bovine eNOS and rat nNOS, respectively. In cellular assays for iNOS, this compound has micromolar potency. Furthermore, two compounds ( 16 and 30 ) demonstrate a reasonable pharmacokinetic profile in rodents. The synthesis, SAR, and biological activity of this novel class of compounds is described.