Author/Authors :
Sharon A. Jackson، نويسنده , , Sukhveen Sahni، نويسنده , , Lan Lee، نويسنده , , Yongyi Luo، نويسنده , , Thaddeus R. Nieduzak، نويسنده , , Guyan Liang، نويسنده , , Yulin Chiang، نويسنده , , Nicola Collar، نويسنده , , David Fink، نويسنده , , Wei He، نويسنده , , Abdelazize Laoui، نويسنده , , Jean Merrill، نويسنده , , Ray Boffey، نويسنده , , Peter Crackett، نويسنده , , Bryan Rees، نويسنده , , Melanie Wong، نويسنده , , Jean-Pierre Guilloteau، نويسنده , , Magali Mathieu، نويسنده , , Sam S. Rebello، نويسنده ,
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 IC50 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.
