Design of isoform-selective inhibitors of nitric oxide synthase

Current Opinion in Chemical Biology

Volumn 2, Issue 4, 1998, Pages 491-500

  Babu, Boga Ramesh ^a   Griffith, Owen W ^a  

^a MEDICAL COLLEGE OF WISCONSIN   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

ARGININE; DRUG DERIVATIVE; ENZYME INHIBITOR; ISOENZYME; NITRIC OXIDE SYNTHASE;

ANIMAL; BINDING SITE; CHEMISTRY; DRUG ANTAGONISM; DRUG DESIGN; HUMAN; METABOLISM; REVIEW;

ANIMALS; ARGININE; BINDING SITES; DRUG DESIGN; ENZYME INHIBITORS; HUMANS; ISOENZYMES; NITRIC OXIDE SYNTHASE;

EID: 0032133353     PISSN: 13675931     EISSN: None     Source Type: Journal    
DOI: 10.1016/S1367-5931(98)80125-7     Document Type: Article

References (87)

1. Stuehr DJ, Griffith OW: Mammalian nitric oxide synthases. Adv Enzymol Rel Areas Mol Biol 1992, 65:287-346.
2. 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? Biochem Biophys Res Commun 1989, 160:881-886.
3. Rees DD, Palmer RMJ, Moncada M: Role of endothelium-derived nitric oxide in the regulation of blood pressure. Proc Natl Acad Sci USA 1989 86:3375-3378.
4. Umans JG, Levi R: Nitric oxide in the regulation of blood flow and arterial pressure. Ann Rev Physiol 1995, 57:771-790.
5. Hibbs JB Jr, Vavrin Z, Taintor RR: L-Arginine is required for the expression of activated macrophage effector mechanism causing selective metabolic inhibition in target cells. J Immunol 1987 138:550-565.
6. Kilbourn RG, Belloni P: Endothelial cell production of nitrogen oxides in response to interferon-γ in combination with tumor necrosis factor, interleukin-1 or endotoxin. J Natl Cane Inst 1990, 82:772-776.
7. G-methyl-L-arginine, an inhibitor of nitric oxide synthesis. Biochem Biophys Res Commun 1990, 172:1132-1138.
8. Gross SS, Wolin MS: Nitric oxide: pathophysiological mechanisms. Annu Rev Physiol 1995, 57:737-769.
9. Kerwin JFK Jr, Heller M: The arginine-nitric oxide pathway: a target for new drugs. Med Res Rev 1994, 14:23-74.
10. Fukuto JM, Chaudhuri G: Inhibition of constitutive and inducible nitric oxide synthase: potential selective inhibition. Annu Rev Pharmacol Toxicol 1995, 35:165-194.
11. Southan GJ, Szabó C: Selective pharmacological inhibition of distinct nitric oxide synthase isoforms. Biochem Pharmacol 1996, 51:383-394.
12. Griffith OW, Gross SS: Inhibitors of nitric oxide synthases. In Methods in Nitric Oxide Research. Edited by Stamler J, Feelish M. New York: John Wiley & Sons; 1996:187-208.
13. Radomski MW, Palmer RMJ, Moncada S: Glucocorticoids inhibit the expression of an inducible, but not the constitutive, nitric oxide synthase in vascular endothelial cells. Proc Natl Acad Sci USA 1990, 87:10043-10047.
14. Ding M, Zhang M, Wong JL, Rogers NE, Ignarro LJ, Voskuhl RR: Antisense knockdown of inducible nitric oxide synthase inhibits induction of experimental autoimmune encephalomyelitis in SJL/J mice. J Immunol 1998, 160:2560-2564.
15. Griffith OW, Park KH, Levi R, Gross SS: The role of plasma arginine in nitric oxide synthesis: Studies with arginase-treated guinea pigs and rats. In The Biology of Nitric Oxide (1). Physiological and Clinical Aspects. Edited by Moncada S, Marietta MA, Hibbs JB Jr, Higgs EA. London: Portland Press; 1992:6-9.
16. Bianchi M, Bloom O, Raabe T, Cohen PS, Chesney J, Sherry B, Schmidtmayerova H, Calandra T, Zhang X, Bukrinsky M et al.: Suppression of proinflammatory cytokines in monocytes by teravalent guanylhydrazone. J Exp Med 1996, 183:927-936.
17. Gross SS, Levi R: Tetrahydrobiopterin synthesis: an absolute requirement for cytokine-induced nitric oxide generation by vascular smooth muscle. J Biol Chem 1992, 267:25722-25729.
18. Aranow JS, Wang H, Zhuang J, Fink MP: Effect of human hemoglobin on systemic and regional hemodynamics in a porcine model of endotoxemic shock. Crit Care Med 1996, 24:807-814.
19. Reah G, Bodenham AR, Mallick A: Initial evaluation of diaspirin cross-linked hemoglobin (DCLHb™) as a vasopressor in critically ill patients. Crit Care Med 1997, 25:1480-1488.
20. Lai C-S, Komarov AM: Spin trapping of nitric oxide produced in vivo in septic shock mice. FEBS Lett 1994, 345:120-124.
21. Griffith OW, Stuehr DJ: Nitric oxide synthases: properties and catalytic mechanism. Annu Rev Physiol 1995, 57:707-736.
22. Salvemini D, Korbut R, Änggård E, Vane J: Immediate release of a nitric oxide-like factor from bovine aortic endothelial cells by Escherichia coli lipopolysaccharide. Proc Natl Acad Sci USA 1990, 87:2593-2597.
23. Vromen A, Szabó C, Southan GJ, Salzman AL: Effects of S-isopropylisothiourea, a potent inhibitor of nitric oxide synthase, in severe hemorrhagic shock. J Appl Physiol 1996, 81:707-715.
24. 6-(I-iminoethyl)-L-lysine works prophylactically, but not therapeutically, in this rat model of rheumatoid arthritis. As the authors note, the studies did not address the possibility that inducible nitric oxide synthase (iNOS) inhibitors might be effective against the cyclical episodes of inflammation seen in chronic disease. Nevertheless, these studies raise concerns regarding the efficacy of iNOS inhibitors in arthritis.
25. 6-(1-iminoethyl)-L-lysine blocked indicible nitric oxide (NO) synthase mediated NO formation but did not reduce inflammation or diarrhea in this model.
26. ••] provide a good overview of the use of inducible nitric oxide synthase (iNOS) inhibitors in septic shock, the most fully developed application for such inhibitors.
27. ••] provide a good overview of the use of inducible nitric oxide synthase (iNOS) inhibitors in septic shock, the most fully developed application for such inhibitors. The author's view that endothelial NOS has a role in early shock could be viewed skeptically by many investigators because it is based upon studies in which large amounts of endotoxin were acutely administered to animals; in septic shock endotoxin levels increase gradually, resulting in iNOS induction.
28. Zhang F, Casey RM, Ross ME, Iadecola C: Aminoguanidine ameliorates and L-arginine worsens brain damage from intraluminal middle cerebral artery occlusion. Stroke 1996, 27:317-323.
29. Thomsen LL, Scott JMJ, Topley P, Knowles RG, Keerie AJ, Frend AJ: Selective inhibition of inducible nitric oxide synthase inhibits tumor growth in vivo: studies with 1400W, a novel inhibitor. Cancer Res 1997, 57:3300-3304.
30. Griffith OW, Kilbourn RG: Design of nitric oxide synthase inhibitors and their use to reverse hypotension associated with cancer immunotherapy. Adv Enz Regul 1997, 37:171-194.
31. McCartney-Francis N, Allen JB, Mizel DE, Albina JE, Xie Q-W, Nathan CF, Wahl SM: Suppression of arthritis by an inhibitor of nitric oxide synthase. J Exp Med 1993, 178:749-754.
32. Stefanovic-Racic M, Stadler J, Evans CH: Nitric oxide and arthritis. Arthritis Rheum 1993, 36:1036-1044.
33. Yamada T, Sartor RB, Marshall S, Specian RD, Grisham MB: Mucosal injury and inflammation in a model of chronic granulomatous colitis in rats. Gastroenterology 1993, 104:759-771.
34. McDaniel ML, Kwon G, Hill JR, Marshall CA, Corbett JA: Cytokines and nitric oxide in islet inflammation and diabetes. Proc Soc Expl Bio Med 1996, 211:24-32.
35. Parkinson JF, Mitrovic B, Merrill JE: The role of nitric oxide in multiple sclerosis. J Mol Med 1997, 75:174-186. There is conflicting data on the role of inducible nitric oxide (NO) synthase and NO in multiple sclerosis. As this review points out, NO, or its product peroxynitrite, may be an important cytotoxin, but NO is also immunosuppres-sive.
36. + channels, glutamate release, and NMDA receptors mediates delayed neurodegeneration through nitric oxide formation. J Neurosci 1996, 16:5004-5013.
37. Lassen LH, Ashina M, Christiansen I, Ulrich V, Olesen J: Nitric oxide synthase inhibition in migraine. Lancet 1997, 349:401-402.
38. Anbar M, Gratt BM: Role of nitric oxide in the physiology of pain. J Pain Symptom Management 1997, 14:225-254. This is a comprehensive survey of evidence linking neuronal nitric oxide (NO) synthase (NOS) and inducible NOS derived NO to pain, particularly in inflammatory joint diseases.
39. Handy RLC, Wallace P, Gaffen ZA, Whitehead KJ, Moore PK: The antinociceptive effect of 1-(2-trifluoromethylphenyl)imidazole (TRIM), a potent inhibitor of neuronal nitric oxide synthase in vitro, in the mouse. Br J Pharmacol 1995, 116:2349-2350.
40. Dawson VL, Dawson TM: Nitric oxide neurotoxicity. J Chem Neuroanat 1996, 10:179-190.
41. Huang PL, Dawson TM, Bredt DS, Snyder SH, Fishman MC: Targeted disruption of the neuronal nitric oxide synthase gene. Cell 1993, 75:1273-1286.
42. Moore PK, Handy RLC: Selective inhibitors of neuronal nitric oxide synthase - is no NOS really good NOS for the nervous system. Trends Pharmacol 1997, 18:204-211.
43. + by arginine analogs that inhibit nitric oxide synthase. Biochim Biophys Acta 1997, 1324:133-141.
44. Crane BR, Arvai AS, Ghosh DK, Wu C, Getzoff ED, Stuehr DJ, Tainer JA: Structure of nitric oxide synthase oxygenase dimer with pterin and substrate. Science 1998, 27:2121-2126. This paper presents the first description of the X-ray crystallographic structure of the key nitric oxide synthase oxygenase domain in a presumably catalytically active conformation.
45. Frey C, Narayanan K, McMillan K, Spack L, Gross SS, Masters BSS, Griffith OW: L-Thiocitrulline: a stereospecific, heme-binding inhibitor of nitric oxide synthases. J Biol Chem 1994, 269:26083-26091.
46. Salerno JC, Frey C, McMillan M, Williams RF, Masters BSS, Griffith OW: Characterization by electron paramagnetic resonance of the interactions of L-arginine and L-thiocitrulline with the heme cofactor region of nitric oxide synthase. J Biol Chem 1995, 270:27423-27428.
47. Wolff DJ, Gribin BJ: The inhibition of the constitutive and inducible nitric oxide synthase isoforms by indazole agents. Arch Biochem Biophys 1994, 311:300-306.
48. Iyengar R, Stuehr DJ, Marietta MA: Macrophage synthesis of nitrite, nitrate, and N-nitrosamines: Precursors and role of the respiratory burst. Proc Natl Acad Sci USA 1987, 84:6369-6373.
49. G-cyclopropyl-L-arginine: Two novel inhibitors of macrophage nitric oxide synthase. J Med Chem 1992 35:1137-1144.
50. ω-hydroxy-L-arginine are inhibitors, but not inactivators, of neuronal and macrophage nitric oxide synthases. Bioorg Med Chem 1997 5:1601-1608. This paper provides a good discussion of factors in the guanidinium region of the L-arginine-binding site that may control reactivity and selectivity.
51. 5-(1-lmino-3-butenyl)-L-ornithine: a neuronal isoform selective inhibitor of nitric oxide synthase J Biol Chem 1998, 273:8882-8889. This paper reports a mechanism-based arginine analog inactivator that both binds and reacts with isoform selectivity.
52. Klatt P, Schmidt K, Brunner F, Mayer B: Inhibitors of brain nitric oxide synthase, binding kinetics, metabolism, and enzyme inactivation. J Biol Chem 1994, 269:1674-1680.
53. G-nitroarginine. Biochemistry 1993, 32:8512-8517.
54. Umans JG, Samsel RW: L-Canavanine selectively augments contraction in aortas from endotoxemic rats. Eur J Pharmacol 1992, 210:343-346.
55. Furfine ES, Harmon MF, Paith JE, Knowles RG, Salter M, Kiff RJ, Duffy C, Hazelwood R, Oplinger JA, Garvey EP: 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 1994, 269:26677-26683.
56. Narayanan K, Spack L, McMillan K, Kilbourn RG, Hayward MA, Masters BSS, Griffith OW: S-Alkyl-L-thiocitrullines, potent steroselective inhibitiors of nitric oxide synthase with strong pressor activity in vivo. J Biol Chem 1995, 270:11103-11110.
57. Reif DW, McCreedy SA: N-Nitro-L-arginine and N-monomethyl-L-arginine exhibit a different pattern of inactivation toward the three nitric oxide synthases. Arch Biochem Biophys 1995, 320:170-176.
58. G-nitro-L-arginine. Br J Pharmacol 1996, 118:1433-1440.
59. G-methylarginine requires NADPH-dependent hydroxylation. J Med Chem 1993, 36:491-496.
60. G-methyl-L-arginine: evidence for heme loss. Biochemistry 1994, 33:14784-14791.
61. McCall TB, Feelisch M, Palmer RM, Moncada S: Identification of N-iminoethyl-L-ornithine as an irreversible inhibitor of nitric oxide synthase in phagocytic cells. Br J Pharmacol 1991, 102:234-238.
62. G-methylarginine. Biochem Biophys Res Commun 1990, 170:96-103.
63. G-amino-L-arginine. Arch Biochem Biophys 1996, 325:227-234.
64. W-allyl-L-arginine. J Am Chem Soc 1997, 119:10888-10902. This paper reports the design and characterization of an interesting mechanism-based inhibitor.
65. 6-(1-lminoethyl)lysine: a selective inhibitor of inducible nitric oxide synthase. J Med Chem 1994, 37:3886-3888.
66. Hallinan EA, Tsymbalov S, Finnegan PM, Moore WM, Jerome GM, Currie MG, Pitzele BS: 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 1998, 41:775-777. This is the first report of an inhibitor that exhibits good isoform selectivity by targeting a defined binding region outside of the L-arginine guanidinium pocket.
67. Chen Y, Rosazza JPN: Oligopeptides as substrates and inhibitors for a new constitutive nitric oxide synthase from rat cerebellum. Biochem Biophys Res Commun 1996, 224:303-308.
68. Arima T, Kitamura Y, Nishiya T, Takagi H, Nomura Y: Kyotorphin (L-tyrosyl-L-arginine) as a possible substrate for inducible nitric oxide synthase in rat glial cells. Neurosci Lett 1996, 212:1-4.
69. ω-nitroarginine-and phenylalanine-containing dipeptides and dipeptide esters. J Med Chem 1997, 40:2813-2817.
70. Corbett JA, Tilton RG, Chang K, Hasan KS, Ido Y, Wang JL, Sweetland MA, Lancaster JR Jr, Willamson JR, McDaniel ML: Aminoguanidine, a novel inhibitor of nitric oxide formation, prevents diabetic vascular dysfunction. Diabetes 1992, 41:552-556.
71. Wolff DJ, Gauld DS, Neulander MJ, Southan G: Inactivation of nitric oxide synthase by substituted aminoguanidines and aminoisothioureas. J Pharmacol Exp Ther 1997, 283:265-273.
72. 50) of an enzymatic reaction. Biochem Pharmacol 1973 22:3099-3108.
73. Wolff DJ, Lubeskie A: Aminoguanidine is an isoform-selective, mechanism-based inactivator of nitric oxide synthase. Arch Biochem Biophys 1995, 316:290-301.
74. Ruetten H Thiemermann C: Prevention of the expression of inducible nitric oxide synthase by aminoguanidine or aminoethyl-isothiourea in macrophages and in the rat Biochem Biophys Res Commun 1996, 225:525-530.
75. Ruetten H, Southan GJ, Abate A, Thiemermann C: Attenuation of endotoxin-induced multiple organ dysfunction by 1-amino-2-hydroxy-guanidine, a potent inhibitor of inducible nitric oxide synthase. Br J Pharmacol 1996, 118:261-270.
76. Garvey EP, Oplinger JA, Tanoury GJ, Sherman PA, Fowler M, Marshall S, Harmon MF, Paith JE, Furfine ES: Potent and selective inhibition of human nitric oxide synthases-Inhibition by non-amino acid isothioureas. J Biol Chem 1994, 269:26669-26676.
77. Southan GJ, Szabó C, Thiemermann C: Isothioureas: potent inhibitors of nitric oxide synthases with variable isoform selectivity. Br J Pharmacol 1995, 114:510-516.
78. Babu BR, Griffith OW: Acetylenic isothioureas: potent inhibitors of nitric oxide synthase [abstract]. FASEB J 1996, 10:1399.
79. Southan GJ, Zingarelli B, O'Connor M, Salzman AL, Szabó G: Spontaneous rearrangement of aminoalkylisothioureas into mercaptoalkylguanidines, a novel class of nitric oxide synthase inhibitors with selectivity towards the inducible isoform. Br J Pharmacol 1996, 117:619-632.
80. Shearer BG, Lee S, Oplinger JA, Frick LW, Garvey EP, Furfine ES: Substituted N-phenylisothioureas: potent inhibitors of human nitric oxide synthase with neuronal isoform selectivity. J Med Chem 1997, 40:1901-1905. Although the neuronal nitric oxide synthase-selective inhibitor defined by these studies did not prove pharmacologically useful, the authors provide a wealth of structure/activity relationship data defining factors that affect interactions of these compounds with the L-arginine binding site.
81. Garvey EP, Oplinger JA, Furfine ES, Kiff PJ, Laszlo F, Whittle BJR, Knowles RG: 1400W is a slow, tight binding and highly selective inhibitor of inducible nitirc oxide synthase in vitro and in vivo. J Biol Chem 1997, 272:4959-4963. This report provides the basic enzymological data on 1400W, the most selective inducible nitric oxide synthase (iNOS) inhibitor reported to date. In addition, the authors provide preliminary biological data (see also [29]), as well as a useful summary of the rationale guiding the design of this highly iNOS selective inhibitor.
82. 18F]fluoroethyl)isothiourea, as potential positron emission tomography tracers. J Med Chem 1996, 39:5110-5118.
83. Moore WM, Webber RK, Fok KF, Jerome GM, Connor JR, Manning FT, Wyatt PS, Misko TP, Tjoeng FS, Currie MG: 2-Iminopiperidine and other 2-iminoazaheterocycles as potent inhibitors of human nitric oxide synthase isoforms. J Med Chem 1996, 39:669-672.
84. Webber RK, Metz S, Moore WM, Connor JR, Currie MG, Fok KF, Hagen TJ, Hansen DW, Jerome GM, Manning PT et al.: Substituted 2-iminopiperidines as inhibitors of human nitric oxide synthase isoforms. J Med Chem 1998, 41:96-101 In this paper, the authors provide a wealth of structure/activity relationship data on these nonamino acid inhibitors.
85. Zhang ZG, Reif D, Macdonald J, Tang WX, Kamp DK, Gentile RJ, Shakespear WC, Murray RJ, Chopp M: 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 1996, 16:599-604.
86. 2+/calmodulin domain.
87. Jeffrey SR, Snyder SH: PIN: an associated protein inhibitor of neuronal nitric oxide synthase Science 1996, 274:774-777.