Heteroaromatic-aminomethyl quinolones: potent and selective iNOS inhibitors.

Abstract

The overproduction of nitric oxide during the biological response to inflammation by the nitric oxide synthase (NOS) enzymes have been implicated in the pathology of many diseases. By removal of the amide core from uHTS-derived quinolone 4, a new series highly potent heteroaromatic-aminomethyl quinolone iNOS inhibitors 8 were identified. SAR studies led to identification of piperazine 22 and pyrimidine 32, both of which reduced plasma nitrates following oral dosing in a mouse lipopolysaccharide challenge assay.

• Authors: Sergio G Durón, Andrew Lindstrom, Céline Bonnefous, Hui Zhang, Xiaohong Chen, Kent T Symons, Marciano Sablad, Natasha Rozenkrants, Yan Zhang, Li Wang, Nahid Yazdani, Andrew K Shiau, Stewart A Noble, Peter Rix, Tadimeti S Rao, Christian A Hassig, Nicholas D Smith
• Journal: Bioorganic & medicinal chemistry letters (Bioorg Med Chem Lett) Vol. 22 Issue 2 Pg. 1237-41 (Jan 15 2012) ISSN: 1464-3405 [Electronic] England
• PMID: 22182498 (Publication Type: Journal Article)
• Copyright: Copyright © 2011 Elsevier Ltd. All rights reserved.

Chemical References

• Enzyme Inhibitors
• Ligands
• Quinolones
• Nitric Oxide Synthase Type II

Topics

• Crystallography, X-Ray
• Dose-Response Relationship, Drug
• Enzyme Inhibitors (chemical synthesis, chemistry, pharmacology)
• Humans
• Ligands
• Models, Molecular
• Molecular Structure
• Nitric Oxide Synthase Type II (antagonists & inhibitors, metabolism)
• Quinolones (chemical synthesis, chemistry, pharmacology)
• Stereoisomerism
• Structure-Activity Relationship