Heteroaromatic-aminomethyl quinolones: potent and selective iNOS inhibitors

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

doi:10.1016/j.bmcl.2011.11.073

Heteroaromatic-aminomethyl quinolones: potent and selective iNOS inhibitors

Bioorg Med Chem Lett. 2012 Jan 15;22(2):1237-41. doi: 10.1016/j.bmcl.2011.11.073. Epub 2011 Nov 25.

Authors

Sergio G Durón¹, 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

Affiliation

¹ Afraxis, La Jolla, CA 92037, United States.

PMID: 22182498
DOI: 10.1016/j.bmcl.2011.11.073

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.

MeSH terms

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

Substances

Enzyme Inhibitors
Ligands
Quinolones
Nitric Oxide Synthase Type II