jm900173b_si_001.pdf (5.35 MB)
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
journal contributionposted on 2009-05-14, 00:00 authored by Céline Bonnefous, Joseph E. Payne, Jeffrey Roppe, Hui Zhuang, Xiaohong Chen, Kent T. Symons, Phan M. Nguyen, Marciano Sablad, Natasha Rozenkrants, Yan Zhang, Li Wang, Daniel Severance, John P. Walsh, Nahid Yazdani, Andrew K. Shiau, Stewart A. Noble, Peter Rix, Tadimeti S. Rao, Christian A. Hassig, Nicholas D. Smith
There are three isoforms of dimeric nitric oxide synthases (NOS) that convert arginine to citrulline and nitric oxide. Inducible NOS is implicated in numerous inflammatory diseases and, more recently, in neuropathic pain states. The majority of existing NOS inhibitors are either based on the structure of arginine or are substrate competitive. We describe the identification from an ultra high-throughput screen of a novel series of quinolinone small molecule, nonarginine iNOS dimerization inhibitors. SAR studies on the screening hit, coupled with an in vivo lipopolysaccharide (LPS) challenge assay measuring plasma nitrates and drug levels, rapidly led to the identification of compounds 12 and 42potent inhibitors of the human and mouse iNOS enzyme that were highly selective over endothelial NOS (eNOS). Following oral dosing, compounds 12 and 42 gave a statistical reduction in pain behaviors in the mouse formalin model, while 12 also statistically reduced neuropathic pain behaviors in the chronic constriction injury (Bennett) model.