Discovery of inducible nitric oxide synthase (iNOS) inhibitor development candidate KD7332, part 1: Identification of a novel, potent, and selective series of quinolinone iNOS dimerization inhibitors that are orally active in rodent pain models.

摘要: There are three isoforms of dimeric nitric oxide synthases (NOS) that convert arginine to citrulline and oxide. Inducible NOS is implicated in numerous inflammatory diseases and, more recently, neuropathic pain states. The majority existing inhibitors either based on the structure or substrate competitive. We describe identification from an ultra high-throughput screen a novel series quinolinone small molecule, nonarginine iNOS dimerization inhibitors. SAR studies screening hit, coupled with vivo lipopolysaccharide (LPS) challenge assay measuring plasma nitrates drug levels, rapidly led compounds 12 42—potent human mouse enzyme were highly selective over endothelial (eNOS). Following oral dosing, 42 gave statistical reduction behaviors formalin model, while also statistically reduced chronic constrictio...