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

  title={KLYP956 Is a Non-Imidazole-Based Orally Active Inhibitor of Nitric-Oxide Synthase Dimerization},
  author={Kent T Symons and Mark Eben Massari and Phan M Nguyen and Tom T. Lee and Jeffrey Roger Roppe and C{\'e}line Bonnefous and Joseph E. Payne and Nicholas D. Smith and Stewart A. Noble and Marciano Sablad and Natasha Rozenkrants and Yan Zhang and Tadimeti S Rao and Andrew K. Shiau and Christian Andrew Hassig},
  journal={Molecular Pharmacology},
  pages={153 - 162}
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… 

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The crystal structure of inhibitor bound to the monomeric iNOS oxygenase domain revealed inhibitor-heme coordination and substantial perturbation of the substrate binding site and theDimerization interface, indicating that this small molecule acts by allosterically disrupting protein-protein interactions at the dimer interface.
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Bulky imidazoles like clotrimazole block NO synthesis by inhibiting assembly of the iNOS dimer, revealing a new means to control cellular NO synthesis.
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The selectivity for inhibiting dimerization of iNOS versus endothelial and neuronal NOS suggests that the energetics and kinetics of monomer-dimer equilibria are substantially different for the mammalian NOS isoforms.
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