1. Heteroaromatic-aminomethyl quinolones: Potent and selective iNOS inhibitors
- Author
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Nahid Yazdani, Peter J. Rix, Sergio G. Duron, Celine Bonnefous, Xiaohong Chen, Kent T. Symons, Yan Zhang, Hui Zhang, Li Wang, Stewart A. Noble, Nicholas D. Smith, Christian A. Hassig, Andrew K. Shiau, Natasha Rozenkrants, Tadimeti S. Rao, Andrew K. Lindstrom, and Marciano Sablad
- Subjects
Models, Molecular ,Pyrimidine ,medicine.drug_class ,Clinical Biochemistry ,Nitric Oxide Synthase Type II ,Pharmaceutical Science ,Inflammation ,Quinolones ,Pharmacology ,Crystallography, X-Ray ,Ligands ,Biochemistry ,Nitric oxide ,Structure-Activity Relationship ,chemistry.chemical_compound ,Drug Discovery ,medicine ,Humans ,Enzyme Inhibitors ,Overproduction ,Molecular Biology ,chemistry.chemical_classification ,Dose-Response Relationship, Drug ,Molecular Structure ,biology ,Organic Chemistry ,Stereoisomerism ,Quinolone ,Nitric oxide synthase ,Piperazine ,Enzyme ,chemistry ,biology.protein ,Molecular Medicine ,medicine.symptom - 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.
- Published
- 2012
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