A series of Nω-nitro-Nω’-substituted
guanidines has been prepared as potential inhibitors of the human Nitric Oxide
Synthase (NOS) isoforms. The reported utility of amino-guanidine and nitroarginine
in iNOS inhibition points to a potential similar utility for analogs of
nitro-guanidine. The compound library was tested against the three isoforms of
Nitric Oxide Synthase (eNOS, iNOS and nNOS). Several candidates showed
excellent activity and good selectivity for nNOS. One particular compound even
demonstrated good selectivity for iNOS. The potential usefulness of such
selective inhibitors is discussed.
References
[1]
Laskin, J.D. and Laskin, D.L. (1999) Cellular and Molecular Biology of Nitric Oxide. Marcel Dekker, New York.
[2]
Loscalzo, J. (2013) The Identification of Nitric Oxide as Endothelium-Derived Relaxing Factor. Circulation Research, 113, 100-103. http://dx.doi.org/10.1161/CIRCRESAHA.113.301577
[3]
Rochette, L., Lorin, J., Zeller, M., Guilland, J.-C., Lorgis, L., Cottin, Y. and Vergely, C. (2013) Nitric Oxide Synthase Inhibition and Oxidative Stress in Cardiovascular Diseases: Possible Therapeutic Targets? Pharmacology & Therapeutics, 140, 239-257. http://dx.doi.org/10.1016/j.pharmthera.2013.07.004
[4]
Marletta, M.A. (1993) Nitric Oxide Synthase Structure and Mechanism. Journal of Biological Chemistry, 268, 12231-12234.
[5]
Kerwin Jr., J.F., Lancaster Jr., J.R. and Feldman, P.L. (1995) Nitric Oxide: A New Paradigm for Second Messengers. Journal of Medicinal Chemistry, 38, 4342-4362. http://dx.doi.org/10.1021/jm00022a001
[6]
Stuehr, D.J. and Griffith, O.W. (1992) Mammalian Nitric Oxide Synthases. Advances in Enzymology and Related Areas of Molecular Biology, 65, 287-346.
[7]
Forstermann, U., Pollock, J.S., Schmidt, H.H., Heller, M. and Murad, F. (1991) Calmodulin-Dependent EndotheliumDerived Relaxing Factor/Nitric Oxide Synthase Activity Is Present in the Particulate and Cytosolic Fractions of Bovine Aortic Endothelial Cells. Proceedings of the National Academy of Sciences USA, 88, 1788-1792.
http://dx.doi.org/10.1073/pnas.88.5.1788
[8]
Schmidt, H.H. and Walter, U. (1994) NO at Work. Cell, 78, 919-925.
http://dx.doi.org/10.1016/0092-8674(94)90267-4
[9]
MacMicking, J., Xie, Q.W. and Nathan, C. (1997) Nitric Oxide and Macrophage Function. Annual Review of Immunology, 15, 323-350. http://dx.doi.org/10.1146/annurev.immunol.15.1.323
[10]
Wolff, D.J. and Luneskie, A. (1995) Aminoguanidine Is an Isoform-Selective, Mechanism-Based Inactivator of Nitric Oxide Synthase. Archives of Biochemistry and Biophysics, 316, 290-301. http://dx.doi.org/10.1006/abbi.1995.1040
[11]
Malaviya, R., Venosa, A., Hall, L., Gow, A.J., Sinko, P.J., Laskin J.D. and Laskin, D.L. (2012) Attenuation of Acute Nitrogen Mustard-Induced Lung Injury, Inflammation and Fibrogenesis by a Nitric Oxide Synthase Inhibitor. Toxicology and Applied Pharmacology, 265, 279-291. http://dx.doi.org/10.1016/j.taap.2012.08.027
[12]
Cinelli, M.A., Li, H., Chreifi, G., Martásek P., Roman, L.J., Poulos, T.L. and Silverman, R.B. (2014) Simplified 2-Aminoquinoline-Based Scaffold for Potent and Selective Neuronal Nitric Oxide Synthase Inhibition. Journal of Medicinal Chemistry, 57, 1513-1530. http://dx.doi.org/10.1021/jm401838x
[13]
Misra, S., Kuhad, A. and Chopra, K. (2013) Neurobiological Effect of 7-Nitroindazole, a Neuronal Nitric Oxide Synthase Inhibitor, in Experimental Paradigm of Alzheimer’s Disease. Indian Journal of Experimental Biology, 51, 1086-1093.
[14]
Silverman, R.B. (2009) Design of Selective Neuronal Nitric Oxide Synthase Inhibitors for the Prevention and Treatment of Neurodegenerative Diseases. Accounts of Chemical Research, 42, 439-451.
http://dx.doi.org/10.1021/ar800201v
[15]
Marletta, M.A., (1994) Approaches toward Selective Inhibition of Nitric Oxide Synthase. Journal of Medicinal Chemistry, 37, 1899-1907. http://dx.doi.org/10.1021/jm00039a001
[16]
Gross, S.S., Stuehr, D.J., Aisaka, K., Jaffe, E.A., Levi, R. and Griffith, O.W. (1990) Macrophage and Endothelial Cell Nitric Oxide Synthesis: Cell-Type Selective Inhibition by NG-aminoarginine, NG-nitroarginine and NG-methylarginine. Biochemical and Biophysical Research Communications, 170, 96-103.
http://dx.doi.org/10.1016/0006-291X(90)91245-N
[17]
Speltz, L.M., Walworth, B.L. and Pavlista, A.D. (1990) Substituted Nitro and Cyanoguanidines and Their Uses of Increasing Crop Yields. US Patent 4944788.
[18]
Arotin, R.L., Walworth, B.L. and Marini, M.E. (1987) US Patent 4639268.
[19]
Lutz, A.W. and Rodaway, S.J. (1987) US Patent 4677226.
[20]
Casillas, R.P., Kiser, R.C., Truxall, J.A., Singer, A.W., Shumaker, S.M., Niemuth, N.A., Ricketts, K.M., Mitcheltree, L.W., Castrejon, L.R. and Blank, J.A. (2000) Therapeutic Approaches to Dermatotoxicity by Sulfur Mustard I. Modulation of Sulfur Mustard-Induced Cutaneous Injury in the Mouse Ear Vesicant Model. Journal of Applied Toxicology, 20, S145-S151. http://dx.doi.org/10.1002/1099-1263(200012)20:1+<::AID-JAT665>3.0.CO;2-J
[21]
Young, S.C., Fabio, K.M., Huang, M.T., Saxena, J., Harman, M.P., Guillon, C.D., Vetrano, A.M., Heck, D.E., Flowers II, R.A., Heindel, N.D. and Laskin, J.D. (2012) Investigation of Anticholinergic and Non-Steroidal Anti-Inflammatory Prodrugs Which Reduce Chemically Induced Skin Inflammation. Journal of Applied Toxicology, 32, 135-141.
http://dx.doi.org/10.1002/jat.1645
[22]
Jing, Q., Lil, H., Roman, L.J., Martasek, P., Poulos, T.L. and Silverman, R.B. (2014) Accessible Chiral Linker to Enhance Potency and Selectivity of Neuronal Nitric Oxide Synthase Inhibitors. ACS Medicinal Chemistry Letters, 5, 56-60. http://dx.doi.org/10.1021/ml400381s
[23]
Wolff, D.J. and Datto, G.A. (1992) Identification and Characterization of a Calmodulin-Dependent Nitric Oxide Synthase from GH3 Pituitary Cells. Biochemical Journal, 285, 201-206.
[24]
Wolff, D.J., Mialkowski, K., Richardson, C.F. and Wilson S.R. (2001) C60-Fullerene Monomalonate Adducts Selectively Inactivate Neuronal Nitric Oxide Synthase by Uncoupling the Formation of Reactive Oxygen Intermediates from Nitric Oxide Production. Biochemistry, 40, 37-45. http://dx.doi.org/10.1021/bi0019444
