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Nitric Oxide Synthase Inhibitors I: Substrate Analogs and Heme Ligands

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Nitric Oxide

Part of the book series: Handbook of Experimental Pharmacology ((HEP,volume 143))

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Abstract

The purpose of the current review is to provide the interested investigator with an overview of the most recent advances in the identification, design and development of mechanism-based nitric-oxide synthase (NOS) inhibitors. A thorough review of the early work in this field was previously published by the author (PARKINSON and PHILLIPS 1997).

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References

  • Ara J, Przedborski S, Naini AB, Jackson-Lewis V, Trifiletti RR, Horwitz J, Ischiropoulos H (1998) Inactivation of tyrosine hydroxylase by nitration following exposure to peroxynitrite and 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine. Proc Natl Acad Sci USA 95:7659–7663

    PubMed  CAS  Google Scholar 

  • Babbedge RC, Bland-Ward PA, Hart SL, Moore PK (1993) Inhibition of rat cerebellar nitric oxide synthase by 7-nitro indazole and related substituted indazoles. Br J Pharmacol 110:225–228

    PubMed  CAS  Google Scholar 

  • Beckman JS, Koppenol WH (1996) Nitric oxide, Superoxide, and peroxynitrite: the good, the bad, and ugly. Am J Physiol 271:C1424–C1437

    PubMed  CAS  Google Scholar 

  • Brenner T, Brocke S, Szafer F, Sobel RA, Parkinson JF, Perez DH, Steinman L (1997) Inhibition of nitric oxide synthase for treatment of experimental autoimmune encephalomyelitis. J Immunol 158:2940–2946

    PubMed  CAS  Google Scholar 

  • Bruch-Gerharz D, Ruzicka T, Kolb-Bachofen V (1998) Nitric oxide in human skin: current status and future prospects. J Invest Dermatol 110:1–7

    PubMed  CAS  Google Scholar 

  • Calaycay JR, Kelly TM, MacNaul KL, McCauley ED, Qi H, Grant SK, Griffin PR, Klatt T, Raju SM, Nussler AK, Shah S, Weidner JR, Williams HR, Wolfe GC, Geller DA, Billiar TR, MacCoss M, Mumford RA, Tocci MJ, Schmidt JA, Wong KK, Hutchinson NI (1996) Expression and immunoaffinity purification of human inducible nitric oxide synthase. Inhibition studies with 2-amino-5,6-dihydro-4H-1,3-thiazine. J Biol Chem 271:28212–28219

    PubMed  CAS  Google Scholar 

  • Castagnoli K, Palmer S, Anderson A, Bueters T, Castagnoli N Jr (1997) The neuronal nitric oxide synthase inhibitor 7-nitroindazole also inhibits the monoamine oxidase-B-catalyzed oxidation of 1-methyl-4-phenyl-l,2,3,6-tetrahydropyridine. Chem Res Toxicol 10:364–368

    PubMed  CAS  Google Scholar 

  • Chabin, RM, McCauley E, Calaycay JR, Kelly TM, MacNaul KL, Wolfe GC, Hutchinson NI, Madhusudanaraju S, Schmidt JA, Kozarich JW, Wong KK (1996) Activesite structure analysis of recombinant human inducible nitric oxide synthase using imidazole. Biochemistry 35:9567–9575

    PubMed  CAS  Google Scholar 

  • Cole PA, Robinson CH (1990) Mechanism and inhibition of cytochrome P-450 aromatase. J Med Chem 33:2933–2942

    PubMed  CAS  Google Scholar 

  • Collins JL, Shearer BG, Oplinger JA, Lee S, Garvey EP, Salter M, Duffy C, Burnette TC, Furfine ES (1998) N-phenylamidines as selective inhibitors of human neuronal nitric oxide synthase: structure-activity studies and demonstration of in vivo activity. J Med Chem 41:2858–2871

    PubMed  CAS  Google Scholar 

  • Corbett JA, McDaniel ML (1996) The use of aminoguanidine, a selective iNOS inhibitor, to evaluate the role of nitric oxide in the development of autoimmune diabetes. Methods 10:21–30

    PubMed  CAS  Google Scholar 

  • Crane BR, Arvai AS, Gachhui R, Wu C, Ghosh DK, Getzoff ED, Stuehr DJ, Tainer JA (1997) The structure of nitric oxide synthase oxygenase domain and inhibitor complexes. Science 278:425–431

    PubMed  CAS  Google Scholar 

  • Crane BR, Arvai AS, Ghosh DK, Wu C, Getzoff ED, Stuehr DJ, Tainer JA (1998) Structure of nitric oxide synthase oxygenase dimer with pterin and substrate. Science 279:2121–2126

    PubMed  CAS  Google Scholar 

  • Diefenbach A, Schindler H, Donhauser N, Lorenz E, Laskay T, MacMicking J, Rollinghoff M, Gresser I, Bogdan C (1998) Type 1 interferon (IFNα/β) and type 2 nitric oxide synthase regulate the innate immune response to a protozoan parasite. Immunity 8:77–87

    PubMed  CAS  Google Scholar 

  • Evans CH, Stefanovic-Racic M, Lancaster J (1995) Nitric oxide and its role in orthopaedic disease. Clin Orthop 312:275–294

    PubMed  Google Scholar 

  • Faraci WS, Nagel AA, Verdries KA, Vincent LA, Xu H, Nichols LE, Labasi JM, Salter ED, Pettipher ER (1996) 2-Amino-4-methylpyridine as a potent inhibitor of inducible NO synthase activity in vitro and in vivo Br. J Pharmacol 119: 1101–1108

    CAS  Google Scholar 

  • Fenyk-Melody JE, Garrison AE, Brunnert SR, Weidner JR, Shen F, Shelton BA, Mudgett JS (1998) Experimental autoimmune encephalomyelitis is exacerbated in mice lacking the NOS2 gene. J Immunol 160:2940–2946

    PubMed  CAS  Google Scholar 

  • Fletcher DS, Widmer WR, Luell S, Christen A, Orevillo C, Shah S, Visco D (1998) Therapeutic administration of a selective inhibitor of nitric oxide synthase does not ameliorate the chronic inflammation and tissue damage associated with adjuvantinduced arthritis in rats. J Pharmacol Exp Ther 284:714–721

    PubMed  CAS  Google Scholar 

  • Frey C, Narayanan K, McMillan K, Spack L, Gross SS, Masters BS, Griffith OW (1994) L-Thiocitrulline. A stereospecific, heme-binding inhibitor of nitric-oxide synthases. J Biol Chem 269:26083–26091

    PubMed  CAS  Google Scholar 

  • Furfine ES, Harmon MF, Paith JE, Knowles RG, Salter M, Kiff RJ, Duffy C, Hazel wood R, Oplinger JA, Garvey EP (1994) 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. J Biol Chem 269: 26677–26683

    CAS  Google Scholar 

  • Gachhui R, Ghosh DK, Wu C, Parkinson J, Crane BR, Stuehr DJ (1997) Mutagenesis of acidic residues in the oxygenase domain of inducible nitric-oxide synthase identifies a glutamate involved in arginine binding. Biochemistry 36:5097–5103

    PubMed  CAS  Google Scholar 

  • Garvey EP, Oplinger JA, Tanoury GJ, Sherman PA, Fowler M, Marshall S, Harmon MF, Paith JE, Furfine ES (1994) Potent and selective inhibition of human nitric oxide synthases. Inhibition by non-amino acid isothioureas. J Biol Chem 269:26669–26676

    CAS  Google Scholar 

  • Garvey EP, Oplinger JA, Furfine ES, Kiff RJ, Laszlo F, Whittle BJ, Knowles RG (1997) 1400W is a slow, tight binding, and highly selective inhibitor of inducible nitric-oxide synthase in vitro and in vivo, J Biol Chem 272:4959–4963

    PubMed  CAS  Google Scholar 

  • Gilkeson GS, Mudgett JS, Seldin MF, Ruiz P, Alexander AA, Misukonis MA, Pisetsky DS, Weinberg JB (1997) Clinical and serologic manifestations of autoimmune disease in MRL-lpr/lpr mice lacking nitric oxide synthase type 2. J Exp Med 186: 365–373

    PubMed  CAS  Google Scholar 

  • Grant SK, Green BG, Wang R, Pacholok SG, Kozarich JW (1997) Characterization of inducible nitric-oxide synthase by cytochrome P-450 substrates and inhibitors. Inhibition by chlorzoxazone. J Biol Chem 272(2):977–983

    PubMed  CAS  Google Scholar 

  • Grant SK, Green BG, Stiffey-Wilusz J, Durette PL, Shah SK, Kozarich JW (1998) Structural requirements for human inducible nitric oxide synthase substrates and substrate analogue inhibitors. Biochemistry 37:4174–4180

    PubMed  CAS  Google Scholar 

  • Gray GA, Schott C, Julou-Schaeffer G, Fleming I, Parratt JR, Stoclet JC (1991) The effect of inhibitors of the L-arginine/nitric oxide pathway on endotoxin-induced loss of vascular responsiveness in anaesthetized rats. Br J Pharmacol 103:1218–1224

    PubMed  CAS  Google Scholar 

  • Green BG, Chabin R, Grant SK (1996) The natural product noformycin is an inhibitor of inducible-nitric oxide synthase. Biochem Biophys Res Commun 225:621–626

    PubMed  CAS  Google Scholar 

  • Griffith OW, Kilbourn RG (1996) Nitric oxide synthase inhibitors: amino acids. Methods in Enzymology, 268:375–392

    PubMed  CAS  Google Scholar 

  • Guthikonda RN, Hagmann WK, Maccoss M, et al. (1996a) Substituted 2-acylaminopyridines as inhibitors of nitric oxide synthase, WO patent 96/18617

    Google Scholar 

  • Guthikonda RN, Grant SK, Maccoss M, et al. (1996b) Cyclic amidine analogs as inhibitors of nitric oxide synthase, WO patent 96/14844

    Google Scholar 

  • Hagen TJ, Bergmanis AA, Kramer SW, Fok KF, Schmelzer AE, Pitzele BS, Swenton L, Jerome GM, Kornmeier CM, Moore WM, Branson LF, Connor JR, Manning PT, Currie MG, Hallinan EA (1998) 2-Iminopyrrolidines as potent and selective inhibitors of human inducible nitric oxide synthase. J Med Chem 41:3675–3683

    PubMed  CAS  Google Scholar 

  • Hallinan EA, Tsymbalov S, Finnegan PM, Moore WM, Jerome GM, Currie MG, Pitzele BS (1998) Acetamidine lysine derivative, N-(5(S)-amino-6,7-dihydroxyheptyl)-ethanimidamide dihydrochloride: a highly selective inhibitor of human inducible nitric oxide synthase. J Med Chem 41:775–777

    PubMed  CAS  Google Scholar 

  • Hamilton LC, Warner TD (1998) Interactions between inducible isoforms of nitric oxide synthase and cyclo-oxygenase in vivo: investigations using the selective inhibitors, 1400W and celecoxib. Br J Pharmacol 125:335–340

    PubMed  CAS  Google Scholar 

  • Handy RL, Wallace P, Moore PK (1996) Inhibition of nitric oxide synthase by isothioureas: cardiovascular and antinociceptive effects. Pharmacol Biochem 55:179–184

    CAS  Google Scholar 

  • Hansen DW, Currie MG, Hallinan EA, et al. (1995) Amidino derivatives useful as nitric oxide synthase inhibitors, WO patent 95/11231

    Google Scholar 

  • Hansen DW Jr, Hagen TJ, Kramer SW, et al. (1996a) Nitric oxide synthase inhibitors derived from cyclic amidines, WO patent 96/35677

    Google Scholar 

  • Hansen DW, Jr, Hallinan EA, Hagen TJ, Kramer SW, et al. (1996b) Cyclic amidino agents useful as nitric oxide synthase inhibitors, WO patent 96/33175

    Google Scholar 

  • Hantraye P, Brouillet E, Ferrante R, Palfi S, Dolan R, Matthews RT, Beal MF (1996) Inhibition of neuronal nitric oxide synthase prevents MPTP-induced Parkinsonism in baboons. Nat Med 2:1017–1021

    PubMed  CAS  Google Scholar 

  • Hara H, Huang PL, Panahian N, Fishman MC, Moskowitz MA (1996) Reduced brain edema and infarction volume in mice lacking the neuronal isoform of nitric oxide synthase after transient MCA occlusion. J Cereb Blood Flow Metab 16:605–611

    PubMed  CAS  Google Scholar 

  • Hierholzer C, Harbrecht B, Menezes JM, Kane J, MacMicking J, Nathan CF, Peitzman AB, Billiar TR, Tweardy DJ (1998) Essential role of induced nitric oxide in the initiation of the inflammatory response after hemorrhagic shock. J Exp Med 187: 917–928

    PubMed  CAS  Google Scholar 

  • Hoelscher P, Rehwinkel H, Burton G, Phillips G, Parkinson JF (1997) New imidazole derivatives are nitric oxide synthase inhibitors. WO patent 9715555-A2

    Google Scholar 

  • Huang PL, Dawson TM, Bredt DS, Snyder SH, Fishman MC (1993) Targeted disruption of the neuronal nitric oxide synthase gene. Cell 75:1273–1286

    PubMed  CAS  Google Scholar 

  • Huang Z, Huang PL, Panahian N, Dalkara T, Fishman MC, Moskowitz MA (1994) Effects of cerebral ischemia in mice deficient in neuronal nitric oxide synthase. Science 265:1883–1885

    PubMed  CAS  Google Scholar 

  • Huang Z, Huang PL, Ma J, Meng W, Ayata C, Fishman MC, Moskowitz MA (1996) Enlarged infarcts in endothelial nitric oxide synthase knockout mice are attenuated by nitro-L-arginine. J Cereb Blood Flow Metab 16(5):981–987

    PubMed  CAS  Google Scholar 

  • Jang D, Szabo C, Murreil GA (1996) S-substituted isothioureas are potent inhibitors of nitric oxide biosynthesis in cartilage. Eur J Pharmacol 312:341–347

    PubMed  CAS  Google Scholar 

  • Kerwin JF, Lancaster JR, Feldman PL (1995) Nitric oxide: a new paradigm for second messengers. J Med Chem 38:4343–4362

    PubMed  CAS  Google Scholar 

  • Kilbourn RG, Jubran A, Gross SS, Griffith OW, Levi R, Adams J, Lodato RF (1990) Reversal of endotoxin-mediated shock by N G-methyl-L-arginine, an inhibitor of nitric oxide synthesis. Biochem Biophys Res Commun 172(3):1132–1138

    PubMed  CAS  Google Scholar 

  • Klatt P, Schmidt K, Brunner F, Mayer B (1994a) Inhibitors of brain nitric oxide synthase. Binding kinetics, metabolism, and enzyme inactivation. J Biol Chem 269: 1674–1680

    PubMed  CAS  Google Scholar 

  • Klatt P, Schmid M, Leopold E, Schmidt K, Werner ER, Mayer B (1994b). The pteridine binding site of brain nitric oxide synthase. Tetrahydrobiopterin binding kinetics, specificity, and allosteric interaction with the substrate domain. J Biol 269:13861–13866

    CAS  Google Scholar 

  • Knowles RG, Moncada S (1992) Nitric oxide as a signal in blood vessels. Trends Biochem Sci 17:399–402

    PubMed  CAS  Google Scholar 

  • Laszlo F, Whittle BJ (1997) Actions of isoform-selective and non-selective nitric oxide synthase inhibitors on endotoxin-induced vascular leakage in rat colon. Eur J Pharmacol 334:99–102

    PubMed  CAS  Google Scholar 

  • Macdonald JE (1995) Brain selective antagonists of nitric oxide synthase. Presentation at the 4th Annual International Business Communications Conference on Nitric Oxide; Philadelphia, PA; March 1995

    Google Scholar 

  • Macdonald JE (1996a) Nitric oxide synthase inhibitors. In Annual Reports of Medicinal Chemistry, Bristol, J.A. ed., 221–230

    Google Scholar 

  • Macdonald JE (1996b) Isothiourea derivatives as NO synthase inhibitors. WO patent 96/09286

    Google Scholar 

  • Macdonald JE (1996c) Bicyclic isothiourea derivatives useful in therapy, WO patent 96/24588

    Google Scholar 

  • Macdonald JE, Gentile RJ, Murray RJ (1994) Guanidine derivatives useful in therapy, WO patent 94/21621

    Google Scholar 

  • Macdonald JE, Shakespeare WC, Murray RJ, Matz JR (1996) Bicyclic amidine derivatives as inhibitors of nitric oxide synthetase, WO patent 96/01817

    Google Scholar 

  • MacMicking JD, Nathan C, Horn G, Chartrain N, Fletcher DS, Trumbauer M, Stevens K, Xie QW, Sokol K, Hutchinson N, Chen H, Mudgett JS (1995) Altered responses to bacterial infection and endotoxic shock in mice lacking inducible nitric oxide synthase. Cell 81:641–650

    PubMed  CAS  Google Scholar 

  • Marietta MA (1993) Nitric oxide synthase structure and mechanism. J Biol Chem 268:12231–12234

    Google Scholar 

  • Matthews RT, Beal MF, Fallon J, Fedorchak K, Huang PL, Fishman MC, Hyman BT (1997) MPP+ induced substantia nigra degeneration is attenuated in nNOS knockout mice. Neurobiol Dis 4:114–121

    PubMed  CAS  Google Scholar 

  • Mayer B, Klatt P, Werner ER, Schmidt K (1994) Identification of imidazole as L-arginine-competitive inhibitor of porcine brain nitric oxide synthase. FEBS Letters, 350:199–202

    PubMed  CAS  Google Scholar 

  • McCall TB, Feelisch M, Palmer RM, Moncada S (1991) Identification of N-iminoethyl-L-ornithine as an irreversible inhibitor of nitric oxide synthase in phagocytic cells. Br J Pharmacol 102:234–238

    PubMed  CAS  Google Scholar 

  • McDaniel ML, Corbett JA, Kwon G, Hill JR (1997). A role for nitric oxide and other inflammatory mediators in cytokine-induced pancreatic beta-cell dysfunction and destruction. Adv Exp Med Biol 426:313–319

    PubMed  CAS  Google Scholar 

  • McMillan K, Masters BS (1993) Optical difference spectrophotometry as a probe of rat brain nitric oxide synthase heme-substrate interaction. Biochemistry 32: 9875–9880

    PubMed  CAS  Google Scholar 

  • Misko TP, Moore WM, Kasten TP, Nickols GA, Corbett JA, Tilton RG, McDaniel ML, Williamson JR, Currie MG (1993) Selective inhibition of the inducible nitric oxide synthase by aminoguanidine. Eur J Pharmacol 233:119–125

    PubMed  CAS  Google Scholar 

  • Moncada S, Higgs A (1993) The L-arginine-nitric oxide pathway. N Engl J Med 329: 2002–2012

    PubMed  CAS  Google Scholar 

  • Moore WM, Webber RK, Jerome GM, Tjoeng FS, Misko TP, Currie MG (1994) L-N6-(1-iminoethyl)lysine: a selective inhibitor of inducible nitric oxide synthase. J Med Chem 37:3886–3888

    PubMed  CAS  Google Scholar 

  • Moore WM, Webber RK, Fok KF, Jerome GM, Connor JR, Manning PT, Wyatt PS, Misko TP, Tjoeng FS, Currie MG (1996) 2-Iminopiperidine and other 2-iminoazaheterocycles as potent inhibitors of human nitric oxide synthase isoforms, J Med Chem 39:669–672

    PubMed  CAS  Google Scholar 

  • Nakane M, Klinghofer V, Kuk JE, Donnelly JL, Budzik GP, Pollock JS, Basha F, Carter GW (1995) Novel potent and selective inhibitors of inducible nitric oxide synthase. Mol Pharm 47:831–834

    CAS  Google Scholar 

  • Narayanan K, Griffith OW (1994) Synthesis of L-thiocitrulline, L-homothiocitrulline, and S-methyl-L-thiocitrulline: a new class of potent nitric oxide synthase inhibitors. J Med Chem 37:885–887

    PubMed  CAS  Google Scholar 

  • Narayanan K, Spack L, McMillan K, Kilbourn RG, Hayward MA, Masters BS, Griffith OW (1995) S-alkyl-L-thiocitruHines. Potent stereoselective inhibitors of nitric oxide synthase with strong pressor activity in vivo. J Biol Chem 270:11103–11110

    PubMed  CAS  Google Scholar 

  • Nathan C (1997) Inducible nitric oxide synthase: what difference does it make? J Clin Invest 100:2417–2423

    PubMed  CAS  Google Scholar 

  • Olken NM, Marietta MA (1992) N G-allyl-and N G-cyclopropyl-L-arginine: two novel inhibitors of macrophage nitric oxide synthase. J Med Chem 35:1137–1144

    PubMed  CAS  Google Scholar 

  • Olken NM, Marietta MA (1993) N G-methyl-L-arginine functions as an alternate substrate and mechanism-based inhibitor of nitric oxide synthase. Biochemistry 32:9677–9685

    PubMed  CAS  Google Scholar 

  • Oplinger JA, Garvey EP, Furfine ES, et al. (1996), Acetamidine Derivatives and their use as inhibitors for the nitric oxide synthase, WO patent 96/19440

    Google Scholar 

  • Parkinson JF, Phillips GB (1997) Nitric oxide synthases: enzymology and mechanismbased inhibitors. In: Rubanyi GM, Dzau VJ (eds), The endothelium in clinical practice: source and target of novel therapies. Marcel Dekker Inc., New York, pp 95–124

    Google Scholar 

  • Parkinson JF, Mitrovic B, Merrill JE (1997) The role of nitric oxide in multiple sclerosis. J Mol Med 75:174–186

    PubMed  CAS  Google Scholar 

  • Parrino PE, Laubach VE, Gaughen JR Jr, Shockey KS, Wattsman TA, King RQ Tribble CG, Kron IL (1998) Inhibition of inducible nitric oxide synthase after myocardial ischemia increases coronary flow. Ann Thorac Surg 66:733–739

    PubMed  CAS  Google Scholar 

  • Pelletier JP, Jovanovic D, Fernandes JC, Manning P, Connor JR, Currie MG, Di Battista JA, Martel-Pelletier J (1998) Reduced progression of experimental osteoarthritis in vivo by selective inhibition of inducible nitric oxide synthase. Arthritis Rheum 41:1275–1286

    PubMed  CAS  Google Scholar 

  • Pfeiffer S, Leopold, Schmidt K, Brunner F, Mayer B (1996) Inhibition of nitric oxide synthesis by NG-nitro-L-arginine methyl ester (L-NAME): requirement for bioactivation to the free acid, NG-nitro-L-arginine. Br J Pharmacol 118:1433–1440

    PubMed  CAS  Google Scholar 

  • Rachmilewitz D, Eliakim R, Ackerman Z, Karmeli F (1998) Direct determination of colonic nitric oxide level-a sensitive marker of disease activity in ulcerative colitis. Am J Gastroenterol 93:409–412

    PubMed  CAS  Google Scholar 

  • Raman CS, Li H, Martasek P, Kral V, Masters BSS, Poulos TL (1998). Crystal structure of endothelial constitutive nitric oxide synthase: a paradigm for pterin function involving a novel metal center. Cell 95:939–950

    PubMed  CAS  Google Scholar 

  • Robertson JG, Bernatowicz MS, Dhalla AM, et al. (1995) Inhibition of bovine brain nitric oxide synthase by α-amino and α-carboxyl derivatives of N Gallyl-L-arginine. Bioorg Chem 23:144–151

    CAS  Google Scholar 

  • Rudic RD, Shesely EG, Maeda N, Smithies O, Segal SS, Sessa WC (1998) Direct evidence for the importance of endothelium-derived nitric oxide in vascular remodeling. J Clin Invest 101:731–736

    PubMed  CAS  Google Scholar 

  • Ruetten H, Thiemermann C (1996) Prevention of the expression of inducible nitric oxide synthase by aminoguanidine or aminoethyl-isothiourea in macrophages and in the rat. Biochem Biophys Res Commun 225:525–530

    PubMed  CAS  Google Scholar 

  • Sahrbacher UC, Lechner F, Eugster HP, Frei K, Lassmann H, Fontana A (1998) Mice with an inactivation of the inducible nitric oxide synthase gene are susceptible to experimental autoimmune encephalomyelitis. Eur J Immunol 28:1332–1338

    PubMed  CAS  Google Scholar 

  • Samdani AF, Dawson TM, Dawson VL (1997) Nitric oxide synthase in models of focal ischemia. Stroke 28:1283–1288

    PubMed  CAS  Google Scholar 

  • Schulz JB, Matthews RT, Muqit MM, Browne SE, Beal MF (1995) Inhibition of neuronal nitric oxide synthase by 7-nitroindazole protects against MPTP-induced neurotoxicity in mice. J Neurochem 64:936–939

    PubMed  CAS  Google Scholar 

  • Sennequier N, Stuehr DJ (1998) Antigungal imidazoles block assembly of inducible NO synthase into an active dimer. Nitric Oxide 2, abstract B12, p 92

    Google Scholar 

  • Shearer BG, Lee S, Oplinger JA, Frick LW, Garvey EP, Furfine ES (1997) Substituted N-phenylisothioureas: potent inhibitors of human nitric oxide synthase with neuronal isoform selectivity. J Med Chem 40:1901–1905

    PubMed  CAS  Google Scholar 

  • Shesely EG, Maeda N, Kim HS, Desai KM, Krege JH, Laubach VE, Sherman PA, Sessa WC, Smithies O (1996) Elevated blood pressures in mice lacking endothelial nitric oxide synthase. Proc Natl Acad Sci USA 93:13176–13181

    PubMed  CAS  Google Scholar 

  • Southan GJ, Szabo C (1996) Selective pharmacological inhibition of distinct nitric oxide synthase isoforms, Biochem Pharmacol 51:383–394

    PubMed  CAS  Google Scholar 

  • Southan GJ, Gross SS, Vane JR (1995) Esters and amides of N G-nitro-L-arginine act as prodrugs in their inhibition of inducible nitric oxide synthase. Enzymology and Biochemistry, 4–7

    Google Scholar 

  • Stratman NC, Fiei GJ, Sethy VH (1996) U-19451A: a selective inducible nitric oxide synthase inhibitor, Life Sciences 59:945–951

    PubMed  CAS  Google Scholar 

  • Stuehr DJ (1997) Structure-function aspects in the nitric oxide synthases. Ann. Rev Pharmacol. Toxicol 37:339–359

    CAS  Google Scholar 

  • Sup SJ, Green BG, Grant SK (1994) 2-Iminobiotin is an inhibitor of nitric oxide synthases. Biochem Biophys Res Commun 204:962–968

    PubMed  CAS  Google Scholar 

  • Thomsen LL, Scott JM, Topley P, Knowles RG, Keerie AJ, Frend AJ (1997) Selective inhibition of inducible nitric oxide synthase inhibits tumor growth in vivo: studies with 1400W, a novel inhibitor. Cancer Res 57:3300–3304

    PubMed  CAS  Google Scholar 

  • Tjoeng FS, Fok KF, Webber RK (1995) Amidino derivatives useful as nitric oxide synthase inhibitors, WO patent 95/11014

    Google Scholar 

  • Tsai AL, Berka V, Chen PF, Palmer G (1996) Characterization of endothelial nitricoxide synthase and its reaction with ligand by electron paramagnetic resonance spectroscopy. J Biol Chem 1271:32563–32571

    Google Scholar 

  • Webber RK, Metz S, Moore WM, Connor JR, Currie MG, Fok KF, Hagen TJ, Hansen DW Jr, Jerome GM, Manning PT, Pitzele BS, Toth MV, Trivedi M, Zupec ME, Tjoeng FS (1998) Substituted 2-iminopiperidines as inhibitors of human nitric oxide synthase isoforms. J Med Chem 41(1):96–101

    PubMed  CAS  Google Scholar 

  • Weinberg JB, Granger DL, Pisetsky DS, Seldin MF, Misukonis MA, Mason SN, Pippen AM, Ruiz P, Wood ER, Gilkeson GS (1994) The role of nitric oxide in the pathogenesis of spontaneous murine autoimmune disease: increased nitric oxide production and nitric oxide synthase expression in MRL-lpr/lpr mice, and reduction of spontaneous glomerulonephritis and arthritis by orally administered N G-monomethyl-L-arginine. J Exp Med 179:651–660

    PubMed  CAS  Google Scholar 

  • Wolff DJ, Datto GA, Samatovicz RA, Tempsick RA (1993a) Calmodulin-dependent nitric-oxide synthase. Mechanism of inhibition by imidazole and phenylimidazoles. J Biol Chem 268:9425–9429

    PubMed  CAS  Google Scholar 

  • Wolff DJ, Datto GA, Samatovicz RA (1993b) The dual mode of inhibition of calmodulin-dependent nitric-oxide synthase by antifungal imidazole agents. J Biol Chem 1993 268(13):9430–9436

    PubMed  CAS  Google Scholar 

  • Wray GM, Millar CG, Hinds CJ, Thiemermann C (1998). Selective inhibition of the activity of inducible nitric oxide synthase prevents the circulatory failure, but not the organ injury/dysfunction, caused by endotoxin. Shock 9:329–335

    PubMed  CAS  Google Scholar 

  • Wright CE, Rees DD, Moncada S (1992) Protective and pathological roles of nitric oxide in endotoxin shock. Cardiovasc Res 26:48–57

    PubMed  CAS  Google Scholar 

  • Wu CC, Chen SJ, Szabo C, Thiemermann C, Vane JR (1995) Aminoguanidine attenuates the delayed circulatory failure and improves survival in rodent models of endotoxic shock. Br J Pharmacol 114:1666–1672

    PubMed  CAS  Google Scholar 

  • Yoshida T, Limmroth V, Irikura K, Moskowitz MA (1994) The NOS inhibitor, 7-nitroindazole, decreases focal infarct volume but not the response to topical acetylcholine in pial vessels. J Cereb Blood Flow Metab 14:924–929

    PubMed  CAS  Google Scholar 

  • Zagvazdin Y, Sancesario G, Wang YX, Share L, Fitzgerald ME, Reiner (1996) A Evidence from its cardiovascular effects that 7-nitroindazole may inhibit endothelial nitric oxide synthase in vivo. Eur J Pharmacol 303:61–69

    PubMed  CAS  Google Scholar 

  • Zhang HQ, Fast W, Marietta MA, Martasek P, Silverman RB (1997) Potent and selective inhibition of neuronal nitric oxide synthase by N ω-propyl-L-arginine. J Med Chem 40:3869–3870

    PubMed  CAS  Google Scholar 

  • Zhang ZG, Reif D, Macdonald J, Tang WX, Kamp DK, Gentile RJ, Shakespeare WC, Murray RJ, Chopp M (1996) ARL-17477, a potent and selective neuronal NOS inhibitor decreases infarct volume after transient middle cerebral artery occlusion in rats. J Cereb Blood Flow Metab 16:599–604

    PubMed  CAS  Google Scholar 

  • Zhao W, Tilton RG, Corbett JA, McDaniel ML, Misko TP, Williamson JR, Cross AH, Hickey WF (1996) Experimental allergic encephalomyelitis in the rat is inhibited by aminoguanidine, an inhibitor of nitric oxide synthase. J Neuroimmunol 64: 123–133

    PubMed  CAS  Google Scholar 

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  1. Department of Pharmacology and Toxicology, Karl-Franzens-University of Graz, Universitätsplatz 2, 8010, Graz, Austria

    Bernd Mayer

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© 2000 Springer-Verlag Berlin Heidelberg

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Parkinson, J.F. (2000). Nitric Oxide Synthase Inhibitors I: Substrate Analogs and Heme Ligands. In: Mayer, B. (eds) Nitric Oxide. Handbook of Experimental Pharmacology, vol 143. Springer, Berlin, Heidelberg. https://doi.org/10.1007/978-3-642-57077-3_6

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  • DOI: https://doi.org/10.1007/978-3-642-57077-3_6

  • Publisher Name: Springer, Berlin, Heidelberg

  • Print ISBN: 978-3-642-63026-2

  • Online ISBN: 978-3-642-57077-3

  • eBook Packages: Springer Book Archive

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