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First published on April 13, 2009; DOI: 10.1124/mol.109.055434

0026-895X/09/7601-153-162$20.00
Mol Pharmacol 76:153-162, 2009

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KLYP956 Is a Non-Imidazole-Based Orally Active Inhibitor of Nitric-Oxide Synthase Dimerization

Kent T. Symons, Mark E. Massari, Phan M. Nguyen, Tom T. Lee, Jeffrey Roppe, Céline Bonnefous, Joseph E. Payne, Nicholas D. Smith, Stewart A. Noble, Marciano Sablad, Natasha Rozenkrants, Yan Zhang, Tadimeti S. Rao, Andrew K. Shiau, and Christian A. Hassig

Departments of Biology (K.T.S., M.E.M., P.M.N., T.T.L., A.K.S., C.A.H.), Chemistry (J.R., C.B., J.E.P., N.D.S., S.A.N.), and Pharmacology (M.S., N.R., Y.Z., T.S.R.), Kalypsys, Inc., San Diego, California; and Department of Molecular Biology, the Scripps Research Institute, La Jolla, California (C.A.H.)

Nitric-oxide synthases (NOS) generate nitric oxide (NO) through the oxidation of L-arginine. Inappropriate or excessive production of NO by NOS is associated with the pathophysiology of various disease states. Efforts to treat these disorders by developing arginine mimetic, substrate-competitive NOS inhibitors as drugs have met with little success. Small-molecule-mediated inhibition of NOS dimerization represents an intriguing alternative to substrate-competitive inhibition. An ultra-high-throughput cell-based screen of 880,000 small molecules identified a novel quinolinone with inducible NOS (iNOS) inhibitory activity. Exploratory chemistry based on this initial screening hit resulted in the synthesis of KLYP956, which inhibits iNOS at low nanomolar concentrations. The iNOS inhibitory potency of KLYP956 is insensitive to changes in concentrations of the substrate arginine, or the cofactor tetrahydrobiopterin. Mechanistic analysis suggests that KLYP956 binds the oxygenase domain in the vicinity of the active site heme and inhibits iNOS and neuronal NOS (nNOS) by preventing the formation of enzymatically active dimers. Oral administration of KLYP956 [N-(3-chlorophenyl)-N-((8-fluoro-2-oxo-1,2-dihydroquinolin-4-yl)methyl)-4-methylthiazole-5-carboxamide] inhibits iNOS activity in a murine model of endotoxemia and blocks pain behaviors in a formalin model of nociception. KLYP956 thus represents the first nonimidazole-based inhibitor of iNOS and nNOS dimerization and provides a novel pharmaceutical alternative to previously described substrate competitive inhibitors.

Received for publication February 12, 2009.

Accepted for publication April 13, 2009.

Address correspondence to: Christian A. Hassig, The Scripps Research Institute, 10550 N. Torrey Pines Road, La Jolla, CA 92037. E-mail: hassig{at}scripps.edu






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