Download MendeleyDesign, Synthesis and Characterization of a Novel Class of Coumarin-Based Inhibitors of Inducible Nitric Oxide Synthase
Jackson, S.A., Sahni, S., Lee, L., Luo, Y., Nieduzak, T.R., Liang, G., Chiang, Y., Collar, N., Fink, D., He, W., Laoui, A., Merrill, J., Boffey, R., Crackett, P., Rees, B., Wong, M., Guilloteau, J.P., Mathieu, M., Rebello, S.S.(2005) Bioorg Med Chem 13: 2723
- PubMed: 15781384
- DOI: https://doi.org/10.1016/j.bmc.2005.02.036
- Primary Citation of Related Structures:
2BHJ - PubMed 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.
Organizational Affiliation:
Internal Medicine, Sanofi-Aventis Pharmaceuticals, Bridgewater, NJ08807, USA.
