In the past three decades, nitric oxide has been well established as an important bioactive molecule implicated in regulation of cardiovascular, nervous, and immune systems. Therefore, it is not surprising that much effort has been made to find specific inhibitors of nitric oxide synthases (NOS), the enzymes responsible for production of nitric oxide. Among the many NOS inhibitors developed to date, inhibitors based on derivatives and analogues of arginine are of special interest, as this category includes a relatively high number of compounds with good potential for experimental as well as clinical application. Though this group of inhibitors covers early nonspecific compounds, modern drug design strategies such as biochemical screening and computer-aided drug design have provided NOS-isoform-specific inhibitors. With an emphasis on major advances in this field, a comprehensive list of inhibitors based on their structural characteristics is discussed in this paper. We provide a summary of their biochemical properties as well as their observed effects both in vitro and in vivo. Furthermore, we focus in particular on their pharmacology and use in recent clinical studies. The potential of newly designed specific NOS inhibitors developed by means of modern drug development strategies is highlighted. 1. Introduction Nitric oxide (NO) is a crucial signaling molecule in vertebrates. NO is generated by NOSes. In vertebrates, three isoforms of NOS have been identified: endothelial NOS (eNOS, also referred as NOS3), neuronal NOS (nNOS, also referred as NOS1), and inducible NOS (iNOS, also referred as NOS2). The endothelial isoform is expressed constitutively in the endothelium lining of blood vessels. Neuronal NOS is constitutively expressed as well and primarily located in the central nervous system and skeletal and heart muscle cells. Inducible NOS is expressed in macrophages and some other cell types upon their activation by a wide range of proinflammatory stimuli. The activity of eNOS and nNOS is controlled by the calcium level via calmodulin-calcium interaction. Conversely iNOS has calmodulin bound permanently; this is why its function depends solely on the expression level [1, 2]. All NOSes metabolize L-arginine to L-citrulline and NO via two consecutive NADPH-dependent monooxygenations (Figure 1(a)). The active NOS consists of two identical monomers, each one having reductase and oxygenase domains. The reductase domain contains a NADPH-/NADP- binding site and a two-component (FAD, FMN) electron transport chain to deliver reducing equivalents to the
References
[1]
W. K. Alderton, C. E. Cooper, and R. G. Knowles, “Nitric oxide synthases: structure, function and inhibition,” Biochemical Journal, vol. 357, no. 3, pp. 593–615, 2001.
[2]
S. Daff, “NO synthase: structures and mechanisms,” Nitric Oxide, vol. 23, no. 1, pp. 1–11, 2010.
[3]
H. Ji, S. Tan, J. Igarashi et al., “Selective neuronal nitric oxide synthase inhibitors and the prevention of cerebral palsy,” Annals of Neurology, vol. 65, no. 2, pp. 209–217, 2009.
[4]
J. Loscalzo and G. Welch, “Nitric oxide and its role in the cardiovascular system,” Progress in Cardiovascular Diseases, vol. 38, no. 2, pp. 87–104, 1995.
[5]
S. R. Jaffrey and S. H. Snyder, “Nitric oxide: a neural messenger,” Annual Review of Cell and Developmental Biology, vol. 11, pp. 417–440, 1995.
[6]
C. Bogdan, “Nitric oxide and the immune response,” Nature Immunology, vol. 2, no. 10, pp. 907–916, 2001.
[7]
A. J. Hobbs, A. Higgs, and S. Moncada, “Inhibition of nitric oxide synthase as a potential therapeutic target,” Annual Review of Pharmacology and Toxicology, vol. 39, pp. 191–220, 1999.
[8]
A. C. Tinker and A. V. Wallace, “Selective inhibitors of inducible nitric oxide synthase: potential agents for the treatment of inflammatory diseases?” Current Topics in Medicinal Chemistry, vol. 6, no. 2, pp. 77–92, 2006.
[9]
R. B. Silverman, “Design of selective neuronal nitric oxide synthase inhibitors for the prevention and treatment of neurodegenerative diseases,” Accounts of Chemical Research, vol. 42, no. 3, pp. 439–451, 2009.
[10]
S. Madaford, S. C. Annedi, J. Ramnauth, and S. Rakhit, “Advancements in the development of nitric oxide synthase inhibitors,” in Annual Reports in Medicinal Chemistry, J. E. Macor, Ed., pp. 27–50, Elsevier, 2009.
[11]
E. D. Garcin, A. S. Arvai, R. J. Rosenfeld et al., “Anchored plasticity opens doors for selective inhibitor design in nitric oxide synthase,” Nature Chemical Biology, vol. 4, no. 11, pp. 700–707, 2008.
[12]
H. Ji, H. Li, P. Martásek, L. J. Roman, T. L. Poulos, and R. B. Silverman, “Discovery of highly potent and selective inhibitors of neuronal nitric oxide synthase by fragment hopping,” Journal of Medicinal Chemistry, vol. 52, no. 3, pp. 779–797, 2009.
[13]
M. T. Bedford and S. G. Clarke, “Protein arginine methylation in mammals: who, what, and why,” Molecular Cell, vol. 33, no. 1, pp. 1–13, 2009.
[14]
R. M. J. Palmer, D. D. Rees, D. S. Ashton, and S. Moncada, “L-arginine is the physiological precursor for the formation of nitric oxide in endothelium-dependent relaxation,” Biochemical and Biophysical Research Communications, vol. 153, no. 3, pp. 1251–1256, 1988.
[15]
I. Sakuma, D. J. Stuehr, S. S. Gross, C. Nathan, and R. Levi, “Identification of arginine as a precursor of endothelium-derived relaxing factor,” Proceedings of the National Academy of Sciences of the United States of America, vol. 85, no. 22, pp. 8664–8667, 1988.
[16]
K. Aisaka, S. S. Gross, O. W. Griffith, and R. Levi, “N(G)-methylarginine, an inhibitor of endothelium-derived nitric oxide synthesis, is a potent pressor agent in the guinea pig: does nitric oxide regulate blood pressure in vivo?” Biochemical and Biophysical Research Communications, vol. 160, no. 2, pp. 881–886, 1989.
[17]
C. J. Lowenstein, J. L. Dinerman, and S. H. Snyder, “Nitric oxide: a physiologic messenger,” Annals of Internal Medicine, vol. 120, no. 3, pp. 227–237, 1994.
[18]
A. Calver, J. Collier, and P. Vallance, “Nitric oxide and cardiovascular control,” Experimental Physiology, vol. 78, no. 3, pp. 303–326, 1993.
[19]
J. Zhang and S. H. Snyder, “Nitric-oxide in the nervous-system,” Annual Review of Pharmacology and Toxicology, vol. 35, pp. 213–233, 1995.
[20]
D. W. Reif and S. A. McCreedy, “N-Nitro-L-arginine and N-monomethyl-L-arginine exhibit a different pattern of inactivation toward the three nitric oxide synthases,” Archives of Biochemistry and Biophysics, vol. 320, no. 1, pp. 170–176, 1995.
[21]
N. M. Olken, Y. Osawa, and M. A. Marletta, “Characterization of the inactivation of nitric oxide synthase by N(G)- methyl-L-arginine: evidence for heme loss,” Biochemistry, vol. 33, no. 49, pp. 14784–14791, 1994.
[22]
O. W. Griffith and R. G. Kilbourn, “Nitric oxide synthase inhibitors: amino acids,” in Nitric Oxide, Part A: Sources and Detection of No; No Synthase, A. G. Kartsatos, Ed., vol. 268 of Methods in Enzymology, pp. 375–392, Academic Press, San Diego, 1996.
[23]
K. K. McDonald, R. Rouhani, M. E. Handlogten et al., “Inhibition of endothelial cell amino acid transport System y+ by arginine analogs that inhibit nitric oxide synthase,” Biochimica et Biophysica Acta. Biomembranes, vol. 1324, no. 1, pp. 133–141, 1997.
[24]
S. Schwartz, R. Clare, K. Devereux, and C. Fook Sheung, “Pharmacokinetics, disposition and metabolism of 546C88 (L-N(G)- methylarginine hydrochloride) in rat and dog,” Xenobiotica, vol. 27, no. 12, pp. 1259–1271, 1997.
[25]
T. S. Maurer, Y. Mishra, and H. L. Fung, “Nonlinear pharmacokinetics of L-N-G-methyl-arginine in rats: characterization by an improved HPLC assay,” Biopharmaceutics & Drug Disposition, vol. 20, no. 8, pp. 397–400, 1999.
[26]
S. I. Ueno, A. Sano, K. Kotani, K. Kondoh, and Y. Kakimoto, “Distribution of free methylarginines in rat tissues and in the bovine brain,” Journal of Neurochemistry, vol. 59, no. 6, pp. 2012–2016, 1992.
[27]
Z. Hussein, M. Beerahee, R. Grover et al., “Pharmacokinetics of the nitric oxide synthase inhibitor L-N(G)- methylarginine hydrochloride in patients with septic shock,” Clinical Pharmacology and Therapeutics, vol. 65, no. 1, pp. 1–9, 1999.
[28]
J. G. Umans and R. Levi, “Nitric oxide in the regulation of blood flow and arterial pressure,” Annual Review of Physiology, vol. 57, pp. 771–790, 1995.
[29]
R. G. Kilbourn, A. Jubran, S. S. Gross et al., “Reversal of endotoxin-mediated shock by N(G)-methyl-L-arginine, an inhibitor of nitric oxide synthesis,” Biochemical and Biophysical Research Communications, vol. 172, no. 3, pp. 1132–1138, 1990.
[30]
R. G. Kilbourn, S. S. Gross, A. Jubran et al., “N(G)-methyl-L-arginine inhibits tumor necrosis factor-induced hypotension: implications for the involvement of nitric oxide,” Proceedings of the National Academy of Sciences of the United States of America, vol. 87, no. 9, pp. 3629–3632, 1990.
[31]
R. G. Kilbourn, C. Szabó, and D. L. Traber, “Beneficial versus detrimental effects of nitric oxide synthase inhibitors in circulatory shock: lessons learned from experimental and clinical studies,” Shock, vol. 7, no. 4, pp. 235–246, 1997.
[32]
W. G. Haynes, J. P. Noon, B. R. Walker, and D. J. Webb, “Inhibition of nitric oxide synthesis increases blood pressure in healthy humans,” Journal of Hypertension, vol. 11, no. 12, pp. 1375–1380, 1993.
[33]
J. S. Stamler, E. Loh, M. A. Roddy, K. E. Currie, and M. A. Creager, “Nitric oxide regulates basal systemic and pulmonary vascular resistance in healthy humans,” Circulation, vol. 89, no. 5, pp. 2035–2040, 1994.
[34]
M. Nyberg, S. P. Mortensen, B. Saltin, Y. Hellsten, and J. Bangsbo, “Low blood flow at onset of moderate-intensity exercise does not limit muscle oxygen uptake,” American Journal of Physiology - Regulatory Integrative and Comparative Physiology, vol. 298, no. 3, pp. R843–R848, 2010.
[35]
A. Petros, D. Bennett, and P. Vallance, “Effect of nitric oxide synthase inhibitors on hypotension in patients with septic shock,” Lancet, vol. 338, no. 8782-8783, pp. 1557–1558, 1991.
[36]
A. Petros, G. Lamb, A. Leone, S. Moncada, D. Bennett, and P. Vallance, “Effects of a nitric oxide synthase inhibitor in human with septic shock,” Cardiovascular Research, vol. 28, no. 1, pp. 34–39, 1994.
[37]
R. Grover, D. Zaccardelli, G. Colice, K. Guntupalli, D. Watson, and J. L. Vincent, “An open-label dose escalation study of the nitric oxide synthase inhibitor, N(G)-methyl-L-arginine hydrochloride (546C88), in patients with septic shock,” Critical Care Medicine, vol. 27, no. 5, pp. 913–922, 1999.
[38]
J. Bakker, R. Grover, A. McLuckie et al., “Administration of the nitric oxide synthase inhibitor NG-methyl- L-arginine hydrochloride (546C88) by intravenous infusion for up to 72 hours can promote the resolution of shock in patients with severe sepsis: results of a randomized, double-blind, placebo-controlled multicenter study (study no. 144-002),” Critical Care Medicine, vol. 32, no. 1, pp. 1–12, 2004.
[39]
D. Watson, R. Grover, A. Anzueto et al., “Cardiovascular effects of the nitric oxide synthase inhibitor N G-methyl-L-arginine hydrochloride (546C88) in patients with septic shock: results of a randomized, double-blind, placebo-controlled multicenter study (study no. 144-002),” Critical Care Medicine, vol. 32, no. 1, pp. 13–20, 2004.
[40]
A. López, J. A. Lorente, J. Steingrub et al., “Multiple-center, randomized, placebo-controlled, double-blind study of the nitric oxide synthase inhibitor 546C88: effect on survival in patients with septic shock,” Critical Care Medicine, vol. 32, no. 1, pp. 21–30, 2004.
[41]
L. H. Lassen, M. Ashina, I. Christiansen et al., “Nitric oxide synthase inhibition: a new principle in the treatment of migraine attacks,” Cephalalgia, vol. 18, no. 1, pp. 27–32, 1998.
[42]
M. Ashina, L. H. Lassen, L. Bendtsen, R. Jensen, and J. Olesen, “Effect of inhibition of nitric oxide synthase on chronic tension-type headache: a randomised crossover trial,” Lancet, vol. 353, no. 9149, pp. 287–289, 1999.
[43]
L. H. Lassen, I. Christiansen, H. K. Iversen, I. Jansen-Olesen, and J. Olesen, “The effect of nitric oxide synthase inhibition on histamine induced headache and arterial dilatation in migraineurs,” Cephalalgia, vol. 23, no. 9, pp. 877–886, 2003.
[44]
L. Hjorth Lassen, H. Klingenberg Iversen, and J. Olesen, “A dose-response study of nitric oxide synthase inhibition in different vascular beds in man,” European Journal of Clinical Pharmacology, vol. 59, no. 7, pp. 499–505, 2003.
[45]
L. H. Lassen, B. Sperling, A. R. Andersen, and J. Olesen, “The effect of i.v. L-NG methylarginine hydrochloride (L-NMMA: 546C88) on basal and acetazolamide (Diamox) induced changes of blood velocity in cerebral arteries and regional cerebral blood flow in man,” Cephalalgia, vol. 25, no. 5, pp. 344–352, 2005.
[46]
P. Vallance, A. Leone, A. Calver, J. Collier, and S. Moncada, “Accumulation of an endogenous inhibitor of nitric oxide synthesis in chronic renal failure,” Lancet, vol. 339, no. 8793, pp. 572–575, 1992.
[47]
P. Vallance, A. Leone, A. Calver, J. Collier, and S. Moncada, “Endogenous dimethylarginine as an inhibitor of nitric oxide synthesis,” Journal of Cardiovascular Pharmacology, vol. 20, no. 12, pp. S60–S62, 1992.
[48]
R. H. B？ger, “Asymmetric dimethylarginine, an endogenous inhibitor of nitric oxide synthase, explains the "L-arginine paradox" and acts as a novel cardiovascular risk factor,” Journal of Nutrition, vol. 134, no. 10, pp. S2842–S2847, 2004.
[49]
Y. Komori, G. C. Wallace, and J. M. Fukuto, “Inhibition of purified nitric oxide synthase from rat cerebellum and macrophage by L-arginine analogs,” Archives of Biochemistry and Biophysics, vol. 315, no. 2, pp. 213–218, 1994.
[50]
A. J. Cardounel and J. L. Zweier, “Endogenous methylarginines regulate neuronal nitric-oxide synthase and prevent excitotoxic injury,” Journal of Biological Chemistry, vol. 277, no. 37, pp. 33995–34002, 2002.
[51]
J. T. Kielstein and C. Zoccali, “Asymmetric dimethylarginine: a cardiovascular risk factor and a uremic toxin coming of age?” American Journal of Kidney Diseases, vol. 46, no. 2, pp. 186–202, 2005.
[52]
R. H. B？ger, “The emerging role of asymmetric dimethylarginine as a novel cardiovascular risk factor,” Cardiovascular Research, vol. 59, no. 4, pp. 824–833, 2003.
[53]
T. Teerlink, Z. Luo, F. Palm, and C. S. Wilcox, “Cellular ADMA: regulation and action,” Pharmacological Research, vol. 60, no. 6, pp. 448–460, 2009.
[54]
P. Vallance and J. Leiper, “Cardiovascular biology of the asymmetric dimethylarginine:dimethylarginine dimethylaminohydrolase pathway,” Arteriosclerosis, Thrombosis, and Vascular Biology, vol. 24, no. 6, pp. 1023–1030, 2004.
[55]
S. S. Wolf, “The protein arginine methyltransferase family: an update about function, new perspectives and the physiological role in humans,” Cellular and Molecular Life Sciences, vol. 66, no. 13, pp. 2109–2121, 2009.
[56]
P. K. Moore, O. A. Al-Swayeh, N. W. S. Chong, R. A. Evans, and A. Gibson, “L-N(G)-nitro arginine (L-NOARG), a novel, L-arginine-reversible inhibitor of endothelium-dependent vasodilatation in vitro,” British Journal of Pharmacology, vol. 99, no. 2, pp. 408–412, 1990.
[57]
D. D. Rees, R. M. J. Palmer, R. Schulz, H. F. Hodson, and S. Moncada, “Characterization of three inhibitors of endothelial nitric oxide synthase in vitro and in vivo,” British Journal of Pharmacology, vol. 101, no. 3, pp. 746–752, 1990.
[58]
E. S. Furfine, “Selective inhibition of constitutive nitric oxide synthase by L-NG-nitroarginine,” Biochemistry, vol. 32, no. 33, pp. 8512–8517, 1993.
[59]
W. M. Moore, R. K. Webber, K. F. Fok et al., “Inhibitors of human nitric oxide synthase isoforms with the carbamidine moiety as a common structural element,” Bioorganic and Medicinal Chemistry, vol. 4, no. 9, pp. 1559–1564, 1996.
[60]
E. S. Furfine, M. F. Harmon, J. E. Paith et al., “Potent and selective inhibition of human nitric oxide synthases. Selective inhibition of neuronal nitric oxide synthase by S-methyl-L-thiocitrulline and S-ethyl-L-thiocitrulline,” Journal of Biological Chemistry, vol. 269, no. 43, pp. 26677–26683, 1994.
[61]
P. Klatt, K. Schmidt, F. Brunner, and B. Mayer, “Inhibitors of brain nitric oxide synthase. Binding kinetics, metabolism, and enzyme inactivation,” Journal of Biological Chemistry, vol. 269, no. 3, pp. 1674–1680, 1994.
[62]
K. Schmidt, P. Klatt, and B. Mayer, “Characterization of endothelial cell amino acid transport systems involved in the actions of nitric oxide synthase inhibitors,” Molecular Pharmacology, vol. 44, no. 3, pp. 615–621, 1993.
[63]
P. Kubes, M. Suzuki, and D. N. Granger, “Nitric oxide: an endogenous modulator of leukocyte adhesion,” Proceedings of the National Academy of Sciences of the United States of America, vol. 88, no. 11, pp. 4651–4655, 1991.
[64]
V. L. Dawson, T. M. Dawson, D. A. Bartley, G. R. Uhl, and S. H. Snyder, “Mechanisms of nitric oxide-mediated neurotoxicity in primary brain cultures,” Journal of Neuroscience, vol. 13, no. 6, pp. 2651–2661, 1993.
[65]
K. M. Boje and P. K. Arora, “Microglial-produced nitric oxide and reactive nitrogen oxides mediate neuronal cell death,” Brain Research, vol. 587, no. 2, pp. 250–256, 1992.
[66]
A. Papapetropoulos, G. García-Carde？a, J. A. Madri, and W. C. Sessa, “Nitric oxide production contributes to the angiogenic properties of vascular endothelial growth factor in human endothelial cells,” Journal of Clinical Investigation, vol. 100, no. 12, pp. 3131–3139, 1997.
[67]
M. Ziche, L. Morbidelli, E. Masini et al., “Nitric oxide mediates angiogenesis in vivo and endothelial cell growth and migration in vitro promoted by substance P,” Journal of Clinical Investigation, vol. 94, no. 5, pp. 2036–2044, 1994.
[68]
J. L. Balligand, R. A. Kelly, P. A. Marsden, T. W. Smith, and T. Michel, “Control of cardiac muscle cell function by an endogenous nitric oxide signaling system,” Proceedings of the National Academy of Sciences of the United States of America, vol. 90, no. 1, pp. 347–351, 1993.
[69]
M. A. Tabrizi-Fard and H. L. Fung, “Pharmacokinetics and steady-state tissue distribution of L- and D-isomers of nitroarginine in rats,” Drug Metabolism and Disposition, vol. 24, no. 11, pp. 1241–1246, 1996.
[70]
E. J. Kidd, A. D. Michel, and P. P. A. Humphrey, “Autoradiographic distribution of [3H]L-N(G)-Nitro-arginine binding in rat brain,” Neuropharmacology, vol. 34, no. 1, pp. 63–73, 1995.
[71]
V. L. R. Rao and R. F. Butterworth, “Kinetics, pharmacology, and autoradiographic distribution of L-[3H]nitroarginine binding sites in rat cerebellum,” Journal of Neurochemistry, vol. 66, no. 2, pp. 701–709, 1996.
[72]
S. Pfeiffer, E. Leopold, K. Schmidt, F. Brunner, and B. Mayer, “Inhibition of nitric oxide synthesis by N(G)-nitro-L-arginine methyl ester (L-NAME): requirement for bioactivation to the free acid, N(G)-nitro-L-arginine,” British Journal of Pharmacology, vol. 118, no. 6, pp. 1433–1440, 1996.
[73]
U. Frandsen, J. Bangsbo, M. Sander et al., “Exercise-induced hyperaemia and leg oxygen uptake are not altered during effective inhibition of nitric oxide synthase with NG-nitro-L-arginine methyl ester in humans,” Journal of Physiology, vol. 531, no. 1, pp. 257–264, 2001.
[74]
J. A. M. Avontuur, S. L. C. E. Buijk, and H. A. Bruining, “Distribution and metabolism of N(G)-nitro-L-arginine methyl ester in patients with septic shock,” European Journal of Clinical Pharmacology, vol. 54, no. 8, pp. 627–631, 1998.
[75]
H. Q. Zhang, W. Fast, M. A. Marletta, P. Martasek, and R. B. Silverman, “Potent and selective inhibition of neuronal nitric oxide synthase by N(ω)-propyl-L-arginine,” Journal of Medicinal Chemistry, vol. 40, no. 24, pp. 3869–3870, 1997.
[76]
H. Q. Zhang, R. P. Dixon, M. A. Marletta, D. Nikolic, R. Van Breemen, and R. B. Silverman, “Mechanism of inactivation of neuronal nitric oxide synthase by N(ω)-allyl-L-arginine,” Journal of the American Chemical Society, vol. 119, no. 45, pp. 10888–10902, 1997.
[77]
N. M. Olken and M. A. Marietta, “NG-allyl- and NG-cyclopropyl-L-arginine: two novel inhibitors of macrophage nitric oxide synthase,” Journal of Medicinal Chemistry, vol. 35, no. 6, pp. 1137–1144, 1992.
[78]
D. J. Wolff and A. Lubeskie, “Inactivation of nitric oxide synthase isoforms by diaminoguanidine and NG-amino-L-arginine,” Archives of Biochemistry and Biophysics, vol. 325, no. 2, pp. 227–234, 1996.
[79]
H. Huang, P. Martasek, L. J. Roman, B. S. S. Masters, and R. B. Silverman, “N(ω)-nitroarginine-containing dipeptide amides. Potent and highly selective inhibitors of neuronal nitric oxide synthase,” Journal of Medicinal Chemistry, vol. 42, no. 16, pp. 3147–3153, 1999.
[80]
R. B. Silverman, H. Huang, M. A. Marletta, and P. Martasek, “Selective inhibition of neuronal nitric oxide synthase by N(ω)- nitroarginine- and phenylalanine-containing dipeptides and dipeptide esters,” Journal of Medicinal Chemistry, vol. 40, no. 18, pp. 2813–2817, 1997.
[81]
H. Ji, J. A. Gómez-Vidal, P. Martásek, L. J. Roman, and R. B. Silverman, “Conformationally restricted dipeptide amides as potent and selective neuronal nitric oxide synthase inhibitors,” Journal of Medicinal Chemistry, vol. 49, no. 21, pp. 6254–6263, 2006.
[82]
J. M. Hah, L. J. Roman, P. Martásek, and R. B. Silverman, “Reduced amide bond peptidomimetics. (4S)-N-(4-amino-5-[aminoalkyl]aminopentyl)-N′-nitroguanidines, potent and highly selective inhibitors of neuronal nitric oxide synthase,” Journal of Medicinal Chemistry, vol. 44, no. 16, pp. 2667–2670, 2001.
[83]
J. M. Hah, P. Martásek, L. J. Roman, and R. B. Silverman, “Aromatic reduced amide bond peptidomimetics as selective inhibitors of neuronal nitric oxide synthase,” Journal of Medicinal Chemistry, vol. 46, no. 9, pp. 1661–1669, 2003.
[84]
J. M. Park, T. Higuchi, K. Kikuchi et al., “Selective inhibition of human inducible nitric oxide synthase by S-alkyl-L-isothiocitrulline-containing dipeptides,” British Journal of Pharmacology, vol. 132, no. 8, pp. 1876–1882, 2001.
[85]
B. R. Babu and O. W. Griffith, “N5-(1-imino-3-butenyl)-L-ornithine. A neuronal isoform selective mechanism-based inactivator of nitric oxide synthase,” Journal of Biological Chemistry, vol. 273, no. 15, pp. 8882–8889, 1998.
[86]
E. A. Litzinger, P. Martásek, L. J. Roman, and R. B. Silverman, “Design, synthesis, and biological testing of potential heme-coordinating nitric oxide synthase inhibitors,” Bioorganic and Medicinal Chemistry, vol. 14, no. 9, pp. 3185–3198, 2006.
[87]
R. J. Young, R. M. Beams, K. Carter et al., “Inhibition of inducible nitric oxide synthase by acetamidine derivatives of hetero-substituted lysine and homolysine,” Bioorganic and Medicinal Chemistry Letters, vol. 10, no. 6, pp. 597–600, 2000.
[88]
W. K. Alderton, A. D. R. Angell, C. Craig et al., “GW274150 and GW273629 are potent and highly selective inhibitors of inducible nitric oxide synthase in vitro and in vivo,” British Journal of Pharmacology, vol. 145, no. 3, pp. 301–312, 2005.
[89]
R. Ijuin, N. Umezawa, and T. Higuchi, “Design, synthesis, and evaluation of new type of l-amino acids containing pyridine moiety as nitric oxide synthase inhibitor,” Bioorganic and Medicinal Chemistry, vol. 14, no. 10, pp. 3563–3570, 2006.
[90]
S. Ulhaq, E. C. Chinje, M. A. Naylor, M. Jaffar, I. J. Stratford, and M. D. Threadgill, “S-2-Amino-5-azolylpentanoic acids related to L-ornithine as inhibitors of the isoforms of nitric oxide synthase (NOS),” Bioorganic and Medicinal Chemistry, vol. 6, no. 11, pp. 2139–2149, 1998.
[91]
S. Ulhaq, E. C. Chinje, M. A. Naylor, M. Jaffar, I. J. Stratford, and M. D. Threadgill, “Heterocyclic analogues of L-citrulline as inhibitors of the isoforms of nitric oxide synthase (NOS) and identification of N(δ)-(4,5-dihydrothiazol-2-yl)ornithine as a potent inhibitor,” Bioorganic and Medicinal Chemistry, vol. 7, no. 9, pp. 1787–1796, 1999.
[92]
M. Scheer, A. Grote, A. Chang et al., “BRENDA, the enzyme information system in 2011,” Nucleic Acids Research, vol. 39, no. 1, pp. D670–D676, 2011.
[93]
B. R. Babu and O. W. Griffith, “Design of isoform-selective inhibitors of nitric oxide synthase,” Current Opinion in Chemical Biology, vol. 2, no. 4, pp. 491–500, 1998.
[94]
E. P. Garvey, J. A. Oplinger, G. J. Tanoury et al., “Potent and selective inhibition of human nitric oxide synthases. Inhibition by non-amino acid isothioureas,” Journal of Biological Chemistry, vol. 269, no. 43, pp. 26669–26676, 1994.
[95]
T. J. Hagen, A. A. Bergmanis, S. W. Kramer et al., “2-Iminopyrrolidines as potent and selective inhibitors of human inducible nitric oxide synthase,” Journal of Medicinal Chemistry, vol. 41, no. 19, pp. 3675–3683, 1998.
[96]
J. L. Collins, B. G. Shearer, J. A. Oplinger et al., “N-phenylamidines as selective inhibitors of human neuronal nitric oxide synthase: structure-activity studies and demonstration of in vivo activity,” Journal of Medicinal Chemistry, vol. 41, no. 15, pp. 2858–2871, 1998.
[97]
J. Seo, P. Martásek, L. J. Roman, and R. B. Silverman, “Selective l-nitroargininylaminopyrrolidine and l-nitroargininylaminopiperidine neuronal nitric oxide synthase inhibitors,” Bioorganic and Medicinal Chemistry, vol. 15, no. 5, pp. 1928–1938, 2007.
[98]
M. Sonntag, A. Deussen, and J. Schrader, “Role of nitric oxide in local blood flow control in the anaesthetized dog,” Pflugers Archiv European Journal of Physiology, vol. 420, no. 2, pp. 194–199, 1992.
[99]
G. A. Van Buren, D. Yang, and K. E. Clark, “Estrogen-induced uterine vasodilatation is antagonized by L-nitroarginine methyl ester, an inhibitor of nitric oxide synthesis,” American Journal of Obstetrics and Gynecology, vol. 167, no. 3, pp. 828–833, 1992.
[100]
A. Vials and G. Burnstock, “Effects of nitric oxide synthase inhibitors, L-N(G)-nitroarginine and L-N(G)-nitroarginine methyl ester, on responses to vasodilators of the guinea-pig coronary vasculature,” British Journal of Pharmacology, vol. 107, no. 2, pp. 604–609, 1992.
[101]
J. A. Lorente, L. Landin, R. De Pablo, E. Renes, and D. Liste, “L-arginine pathway in the sepsis syndrome,” Critical Care Medicine, vol. 21, no. 9, pp. 1287–1295, 1993.
[102]
J. A. M. Avontuur, R. P. Tutein Nolthenius, J. W. Van Bodegom, and H. A. Bruining, “Prolonged inhibition of nitric oxide synthesis in severe septic shock: a clinical study,” Critical Care Medicine, vol. 26, no. 4, pp. 660–667, 1998.
[103]
D. H. Yates, S. A. Kharitonov, P. S. Thomas, and P. J. Barnes, “Endogenous nitric oxide is decreased in asthmatic patients by an inhibitor of inducible nitric oxide synthase,” American Journal of Respiratory and Critical Care Medicine, vol. 154, no. 1, pp. 247–250, 1996.
[104]
W. Fast, M. E. Levsky, M. A. Marletta, and R. B. Silverman, “N(ω)-Propargyl-L-arginine and N(ω)-hydroxy-N(ω)-propargyl-L-arginine are inhibitors, but not activators, of neuronal and macrophage nitric oxide synthases,” Bioorganic and Medicinal Chemistry, vol. 5, no. 8, pp. 1601–1608, 1997.
[105]
C. Raoul, A. G. Estévez, H. Nishimune et al., “Motoneuron death triggered by a specific pathway downstream of fas: potentiation by ALS-linked SOD1 mutations,” Neuron, vol. 35, no. 6, pp. 1067–1083, 2002.
[106]
M. H. Caron and C. Alling, “Role of nitric oxide in ethanol-induced up-regulation of muscarinic acetylcholine receptors in SH-SY5Y cells,” Alcoholism: Clinical and Experimental Research, vol. 25, no. 8, pp. 1107–1113, 2001.
[107]
G. R. Cooper, K. Mialkowski, and D. J. Wolff, “Cellular and enzymatic studies of N(ω)-propyl-L-arginine and S-ethyl-N- [4-(trifluoromethyl)phenyl]isothiourea as reversible, slowly dissociating inhibitors selective for the neuronal nitric oxide synthase isoform,” Archives of Biochemistry and Biophysics, vol. 375, no. 1, pp. 183–194, 2000.
[108]
D. Oceandy, E. J. Cartwright, M. Emerson et al., “Neuronal nitric oxide synthase signaling in the heart is regulated by the sarcolemmal calcium pump 4b,” Circulation, vol. 115, no. 4, pp. 483–492, 2007.
[109]
A. Isaak and J. Ellrich, “Neuronal nitric oxide synthase is involved in the induction of nerve growth factor-induced neck muscle nociception,” Headache, vol. 51, no. 5, pp. 734–743, 2011.
[110]
D. Klamer, J. A. Engel, and L. Svensson, “The neuronal selective nitric oxide synthase inhibitor, N ω-propyl-l-arginine, blocks the effects of phencyclidine on prepulse inhibition and locomotor activity in mice,” European Journal of Pharmacology, vol. 503, no. 1–3, pp. 103–107, 2004.
[111]
D. L. Kellogg, J. L. Zhao, and Y. Wu, “Roles of nitric oxide synthase isoforms in cutaneous vasodilation induced by local warming of the skin and whole body heat stress in humans,” Journal of Applied Physiology, vol. 107, no. 5, pp. 1438–1444, 2009.
[112]
J. M. Fukuto, K. S. Wood, R. E. Byrns, and L. J. Ignarro, “N(G)-Amino-L-arginine: a new potent antagonist of L-arginine-mediated endothelium-dependent relaxation,” Biochemical and Biophysical Research Communications, vol. 168, no. 2, pp. 458–465, 1990.
[113]
S. S. Gross, D. J. Stuehr, K. Aisaka, E. A. Jaffe, R. Levi, and O. W. Griffith, “Macrophage and endothelial cell nitric oxide synthesis: cell-type selective inhibition by N(G)-aminoarginine, N(G)-nitroarginine and N(G)-methylarginine,” Biochemical and Biophysical Research Communications, vol. 170, no. 1, pp. 96–103, 1990.
[114]
M. Hecker, D. T. Walsh, and J. R. Vane, “On the substrate specificity of nitric oxide synthase,” FEBS Letters, vol. 294, no. 3, pp. 221–224, 1991.
[115]
R. B. Silverman, H. Huang, and H. Q. Zhang, “Inhibition of nitric oxide synthase by amino acids and dipeptides,” USA patent US6274557B1, Northwestern University, Evanston, Ill, USA, 2001.
[116]
R. B. Silverman, “Selective neuronal nitric oxide synthase inhibitors,” USA patent WO03000198(A2), Northwestern University, 2003.
[117]
N. Kobayashi, T. Higuchi, M. Hirobe, and T. Nagano, “Selective inhibitor for nitrogen monooxide synthase,” Dainippon Pharmaceutical, Japan patent JP10237097(A), 1998.
[118]
N. Kobayashi, T. Higuchi, Y. Urano, K. Kikuchi, M. Hirobe, and T. Nagano, “Dipeptides containing L-arginine analogs: new isozyme-selective inhibitors of nitric oxide synthase,” Biological and Pharmaceutical Bulletin, vol. 22, no. 9, pp. 936–940, 1999.
[119]
N. E. Rogers and L. J. Ignarro, “Constitutive nitric oxide synthase from cerebellum is reversibly inhibited by nitric oxide formed from L-arginine,” Biochemical and Biophysical Research Communications, vol. 189, no. 1, pp. 242–249, 1992.
[120]
K. Narayanan and O. W. Griffith, “Synthesis of L-thiocitrulline, L-homothiocitrulline, and S-methyl-L-thiocitrulline: a new class of potent nitric oxide synthase inhibitors,” Journal of Medicinal Chemistry, vol. 37, no. 7, pp. 885–887, 1994.
[121]
C. Frey, K. Narayanan, K. McMillan et al., “L-thiocitrulline: a stereospecific, heme-binding inhibitor of nitric- oxide synthases,” Journal of Biological Chemistry, vol. 269, no. 42, pp. 26083–26091, 1994.
[122]
K. Narayanan, L. Spack, K. McMillan et al., “S-alkyl-L-thiocitrullines. Potent stereoselective inhibitors of nitric oxide synthase with strong pressor activity in vivo,” Journal of Biological Chemistry, vol. 270, no. 19, pp. 11103–11110, 1995.
[123]
R. Ijuin, N. Umezawa, S. I. Nagai, and T. Higuchi, “Evaluation of 3-substituted arginine analogs as selective inhibitors of human nitric oxide synthase isozymes,” Bioorganic and Medicinal Chemistry Letters, vol. 15, no. 11, pp. 2881–2885, 2005.
[124]
J. Zhang, M. Xu, C. S. Dence, E. L. C. Sherman, T. J. McCarthy, and M. J. Welch, “Synthesis, in vivo evaluation and PET study of a carbon-11 -labeled neuronal nitric oxide synthase (nNOS) inhibitor S-Methyl-L-thiocitrulline,” Journal of Nuclear Medicine, vol. 38, no. 8, pp. 1273–1278, 1997.
[125]
J. Zanzinger, J. Czachurski, and H. Seller, “Neuronal nitric oxide reduces sympathetic excitability by modulation of central glutamate effects in pigs,” Circulation Research, vol. 80, no. 4, pp. 565–571, 1997.
[126]
J. B. Kelley, K. L. Anderson, S. L. Altmann, and Y. Itzhak, “Long-term memory of visually cued fear conditioning: roles of the neuronal nitric oxide synthase gene and cyclic AMP response element-binding protein,” Neuroscience, vol. 174, pp. 91–103, 2011.
[127]
A. Ichihara, E. W. Inscho, J. D. Imig, and L. G. Navar, “Neuronal nitric oxide synthase modulates rat renal microvascular function,” American Journal of Physiology, Renal Physiology, vol. 274, no. 3, pp. F516–F524, 1998.
[128]
R. Komers, T. T. Oyama, J. G. Chapman, K. M. Allison, and S. Anderson, “Effects of systemic inhibition of neuronal nitric oxide synthase in diabetic rats,” Hypertension, vol. 35, no. 2, pp. 655–661, 2000.
[129]
R. Komers, J. N. Lindsley, T. T. Oyama, K. M. Allison, and S. Anderson, “Role of neuronal nitric oxide synthase (NOS1) in the pathogenesis of renal hemodynamic changes in diabetes,” American Journal of Physiology, Renal Physiology, vol. 279, no. 3, pp. F573–F583, 2000.
[130]
T. B. McCall, M. Feelisch, R. M. J. Palmer, and S. Moncada, “Identification of N-iminoethyl-L-ornithine as an irreversible inhibitor of nitric oxide synthase in phagocytic cells,” British Journal of Pharmacology, vol. 102, no. 1, pp. 234–238, 1991.
[131]
W. M. Moore, R. K. Webber, G. M. Jerome, F. S. Tjoeng, T. P. Misko, and M. G. Currie, “L-N6-(1-Iminoethyl)lysine: a selective inhibitor of inducible nitric oxide synthase,” Journal of Medicinal Chemistry, vol. 37, no. 23, pp. 3886–3888, 1994.
[132]
E. A. Hallinan, S. Tsymbalov, C. R. Dorn et al., “Synthesis and biological characterization of L-N6-(1-iminoethyl)lysine 5-tetrazole-amide, a prodrug of a selective iNOS inhibitor,” Journal of Medicinal Chemistry, vol. 45, no. 8, pp. 1686–1689, 2002.
[133]
J. Assreuy, F. Q. Cunha, M. Epperlein et al., “Production of nitric oxide and superoxide by activated macrophages and killing of Leishmania major,” European Journal of Immunology, vol. 24, no. 3, pp. 672–676, 1994.
[134]
J. C. De Graaf, J. D. Banga, S. Moncada, R. M. J. Palmer, P. G. De Groot, and J. J. Sixma, “Nitric oxide functions as an inhibitor of platelet adhesion under flow conditions,” Circulation, vol. 85, no. 6, pp. 2284–2290, 1992.
[135]
D. C. Jenkins, I. G. Charles, L. L. Thomsen et al., “Roles of nitric oxide in tumor growth,” Proceedings of the National Academy of Sciences of the United States of America, vol. 92, no. 10, pp. 4392–4396, 1995.
[136]
J. S. Duffield, L. P. Erwig, X. Q. Wei, F. Y. Liew, A. J. Rees, and J. S. Savill, “Activated macrophages direct apoptosis and suppress mitosis of mesangial cells,” Journal of Immunology, vol. 164, no. 4, pp. 2110–2119, 2000.
[137]
S. Brahmachari, Y. K. Fung, and K. Pahan, “Induction of glial fibrillary acidic protein expression in astrocytes by nitric oxide,” Journal of Neuroscience, vol. 26, no. 18, pp. 4930–4939, 2006.
[138]
J. Y. Zhang, Y. Wang, M. N. Milton, L. Kraus, A. P. Breau, and S. K. Paulson, “Disposition and Pharmacokinetics of L-N6-(1-Iminoethyl)Lysine-5-Tetrazole-Amide, a Selective iNOS Inhibitor, in Rats,” Journal of Pharmaceutical Sciences, vol. 93, no. 5, pp. 1229–1240, 2004.
[139]
J. Y. Zhang, Y. F. Wang, M. N. Milton et al., “Pharmacokinetics, metabolism and excretion of an inhibitor of inducible nitric oxide synthase, L-NIL-TA, in dog,” Xenobiotica, vol. 33, no. 11, pp. 1159–1171, 2003.
[140]
F. László and B. J. R. Whittle, “Actions of isoform-selective and non-selective nitric oxide synthase inhibitors on endotoxin-induced vascular leakage in rat colon,” European Journal of Pharmacology, vol. 334, no. 1, pp. 99–102, 1997.
[141]
J. R. Connor, P. T. Manning, S. L. Settle et al., “Suppression of adjuvant-induced arthritis by selective inhibition of inducible nitric oxide synthase,” European Journal of Pharmacology, vol. 273, no. 1-2, pp. 15–24, 1995.
[142]
J. D. Macmicking, R. J. North, R. Lacourse, J. S. Mudgett, S. K. Shah, and C. F. Nathan, “Identification of nitric oxide synthase as a protective locus against tuberculosis,” Proceedings of the National Academy of Sciences of the United States of America, vol. 94, no. 10, pp. 5243–5248, 1997.
[143]
D. Salvemini, Z. Q. Wang, P. S. Wyatt et al., “Nitric oxide: a key mediator in the early and late phase of carrageenan-induced rat paw inflammation,” British Journal of Pharmacology, vol. 118, no. 4, pp. 829–838, 1996.
[144]
J. P. Pelletier, D. Jovanovic, J. C. Fernandes, et al., “Reduced progression of experimental osteoarthritis in vivo by selective inhibition of inducible nitric oxide synthase,” Arthritis & Rheumatism, vol. 41, no. 7, pp. 1275–1286, 1998.
[145]
M. Dumont, E. Wille, N. Y. Calingasan, C. Nathan, M. F. Beal, and M. T. Lin, “N-iminoethyl-l-lysine improves memory and reduces amyloid pathology in a transgenic mouse model of amyloid deposition,” Neurochemistry International, vol. 56, no. 2, pp. 345–351, 2010.
[146]
J. A. Crowell, V. E. Steele, C. C. Sigman, and J. R. Fay, “Is inducible nitric oxide synthase a target for chemoprevention?” Molecular Cancer Therapeutics, vol. 2, no. 8, pp. 815–823, 2003.
[147]
P. R. Eynott, D. A. Groneberg, G. Caramori et al., “Role of nitric oxide in allergic inflammation and bronchial hyperresponsiveness,” European Journal of Pharmacology, vol. 452, no. 1, pp. 123–133, 2002.
[148]
A. H. Neufeld, S. I. Kawai, S. Das et al., “Loss of retinal ganglion cells following retinal ischemia: the role of inducible nitric oxide synthase,” Experimental Eye Research, vol. 75, no. 5, pp. 521–528, 2002.
[149]
T. T. Hansel, S. A. Kharitonov, L. E. Donnelly et al., “A selective inhibitor of inducible nitric oxide synthase inhibits exhaled breath nitric oxide in healthy volunteers and asthmatics,” The FASEB Journal, vol. 17, no. 10, pp. 1298–1300, 2003.
[150]
H. F. Hodson, R. M. J. Palmer, D. A. Sawyer, et al., “Enzyme inhibitors,” US patent WO9534534(A1), 1995.
[151]
A. R. Baydoun, J. Bertran, S. Thakur, J. Dawson, M. Palacín, and R. G. Knowles, “y+ LAT-1 mediates transport of the potent and selective iNOS inhibitor, GW274150, in control J774 macrophages,” Amino Acids, vol. 31, no. 2, pp. 101–109, 2006.
[152]
A. J. O'Brien, A. J. Wilson, R. Sibbald, M. Singer, and L. H. Clapp, “Temporal variation in endotoxin-induced vascular hyporeactivity in a rat mesenteric artery organ culture model,” British Journal of Pharmacology, vol. 133, no. 3, pp. 351–360, 2001.
[153]
S. Mattiussi, C. Lazzari, S. Truffa et al., “Homeodomain interacting protein kinase 2 activation compromises endothelial cell response to laminar flow: protective role of p21waf1,cip1,sdi1,” PLoS One, vol. 4, no. 8, Article ID e6603, 2009.
[154]
P. K. Chatterjee, E. O. Kvale, N. S. A. Patel, and C. Thiemermann, “GW274150 inhibits nitric oxide production by primary cultures of rat proximal tubular cells,” Medical Science Monitor, vol. 9, no. 10, pp. BR357–BR362, 2003.
[155]
S. Arnhold, A. Fa？bender, F. J. Klinz et al., “NOS-II is involved in early differentiation of murine cortical, retinal and ES cell-derived neurons - An immunocytochemical and functional approach,” International Journal of Developmental Neuroscience, vol. 20, no. 2, pp. 83–92, 2002.
[156]
J. De Alba, N. M. Clayton, S. D. Collins, P. Colthup, I. Chessell, and R. G. Knowles, “GW274150, a novel and highly selective inhibitor of the inducible isoform of nitric oxide synthase (iNOS), shows analgesic effects in rat models of inflammatory and neuropathic pain,” Pain, vol. 120, no. 1-2, pp. 170–181, 2006.
[157]
M. C. McDonald, M. Izumi, S. Cuzzocrea, and C. Thiemermann, “A novel, potent and selective inhibitor of the activity of inducible nitric oxide synthase (GW274150) reduces the organ injury in hemorrhagic shock,” Journal of Physiology and Pharmacology, vol. 53, no. 4 I, pp. 555–569, 2002.
[158]
S. Cuzzocrea, P. K. Chatterjee, E. Mazzon et al., “Beneficial effects of GW274150, a novel, potent and selective inhibitor of iNOS activity, in a rodent model of collagen-induced arthritis,” European Journal of Pharmacology, vol. 453, no. 1, pp. 119–129, 2002.
[159]
P. K. Chatterjee, N. S. A. Patel, A. Sivarajah et al., “GW274150, a potent and highly selective inhibitor of iNOS reduces experimental renal ischemia/reperfusion injury,” Kidney International, vol. 63, no. 3, pp. 853–865, 2003.
[160]
L. Dugo, S. Marzocco, E. Mazzon et al., “Effects of GW274150, a novel and selective inhibitor of iNOS activity, in acute lung inflammation,” British Journal of Pharmacology, vol. 141, no. 6, pp. 979–987, 2004.
[161]
R. Di Paola, E. Mazzon, N. S. A. Patel et al., “Beneficial effects of GW274150 treatment on the development of experimental colitis induced by dinitrobenzene sulfonic acid,” European Journal of Pharmacology, vol. 507, no. 1–3, pp. 281–289, 2005.
[162]
L. Broom, L. Marinova-Mutafchieva, M. Sadeghian, J. B. Davis, A. D. Medhurst, and D. T. Dexter, “Neuroprotection by the selective iNOS inhibitor GW274150 in a model of Parkinson disease,” Free Radical Biology and Medicine, vol. 50, no. 5, pp. 633–640, 2011.
[163]
D. Singh, D. Richards, R. G. Knowles et al., “Selective inducible nitric oxide synthase inhibition has no effect on allergen challenge in asthma,” American Journal of Respiratory and Critical Care Medicine, vol. 176, no. 10, pp. 988–993, 2007.
[164]
J. E. Palmer, F. L. Guillard, B. E. Laurijssens, A. L. Wentz, R. M. Dixon, and P. M. Williams, “A randomised, single-blind, placebo-controlled, adaptive clinical trial of GW274150, a selective iNOS inhibitor, in the treatment of acute migraine,” Cephalalgia, vol. 29, no. 1, p. 124, 2009.
[165]
H. O. H？ivik, B. E. Laurijssens, L. O. Harnisch et al., “Lack of efficacy of the selective iNOS inhibitor GW274150 in prophylaxis of migraine headache,” Cephalalgia, vol. 30, no. 12, pp. 1458–1467, 2010.
[166]
T. D. Rogerson, C. F. Wilkinson, and K. Hetarski, “Steric factors in the inhibitory interaction of imidazoles with microsomal enzymes,” Biochemical Pharmacology, vol. 26, no. 11, pp. 1039–1042, 1977.
[167]
D. D. Rees, R. M. J. Palmer, and S. Moncada, “Role of endothelium-derived nitric oxide in the regulation of blood pressure,” Proceedings of the National Academy of Sciences of the United States of America, vol. 86, no. 9, pp. 3375–3378, 1989.
[168]
D. R. Cheshire, A. ？berg, G. M. K. Andersson et al., “The discovery of novel, potent and highly selective inhibitors of inducible nitric oxide synthase (iNOS),” Bioorganic and Medicinal Chemistry Letters, vol. 21, no. 8, pp. 2468–2471, 2011.
[169]
T. Fullmer, “Rethinking mechanisms of drug discovery,” SciBX, vol. 4, no. 27, 2011.
[170]
H. Huang, P. Martásek, L. J. Roman, and R. B. Silverman, “Synthesis and evaluation of peptidomimetics as selective inhibitors and active site probes of nitric oxide synthases,” Journal of Medicinal Chemistry, vol. 43, no. 15, pp. 2938–2945, 2000.
[171]
S. Ekins, J. Mestres, and B. Testa, “In silico pharmacology for drug discovery: methods for virtual ligand screening and profiling,” British Journal of Pharmacology, vol. 152, no. 1, pp. 9–20, 2007.
[172]
R. V. C. Guido, G. Oliva, and A. D. Andricopulo, “Virtual screening and its integration with modern drug design technologies,” Current Medicinal Chemistry, vol. 15, no. 1, pp. 37–46, 2008.
[173]
L. Hoffer, J. P. Renaud, and D. Horvath, “Fragment-based drug design: computational and experimental state of the art,” Combinatorial Chemistry and High Throughput Screening, vol. 14, no. 6, pp. 500–520, 2011.
[174]
A. C. Tinker, H. G. Beaton, N. Boughton-Smith et al., “1,2-Dihydro-4-quinazolinamines: potent, highly selective inhibitors of inducible nitric oxide synthase which show antiinflammatory activity in vivo,” Journal of Medicinal Chemistry, vol. 46, no. 6, pp. 913–916, 2003.
[175]
H. Ji, B. Z. Stanton, J. Igarashi et al., “Minimal pharmacophoric elements and fragment hopping, an approach directed at molecular diversity and isozyme selectivity. Design of selective neuronal nitric oxide synthase inhibitors,” Journal of the American Chemical Society, vol. 130, no. 12, pp. 3900–3914, 2008.
[176]
S. Ekins, J. Mestres, and B. Testa, “In silico pharmacology for drug discovery: applications to targets and beyond,” British Journal of Pharmacology, vol. 152, no. 1, pp. 21–37, 2007.
[177]
H. Ji, H. Li, M. Flinspach, T. L. Poulos, and R. B. Silverman, “Computer modeling of selective regions in the active site of nitric oxide synthases: implication for the design of isoform-selective inhibitors,” Journal of Medicinal Chemistry, vol. 46, no. 26, pp. 5700–5711, 2003.
[178]
L. G. Fr？hlich, P. Kotsonis, H. Traub et al., “Inhibition of neuronal nitric oxide synthase by 4-amino pteridine derivatives: structure-activity relationship of antagonists of (6R)-5,6,7,8- tetrahydrobiopterin cofactor,” Journal of Medicinal Chemistry, vol. 42, no. 20, pp. 4108–4121, 1999.
[179]
H. Matter, P. Kotsonis, O. Klingler et al., “Structural requirements for inhibition of the neuronal nitric oxide synthase (NOS-I): 3D-QSAR analysis of 4-oxo- and 4-amino-pteridine-based inhibitors,” Journal of Medicinal Chemistry, vol. 45, no. 14, pp. 2923–2941, 2002.
