Nitric oxide synthase inhibitors: A review of patents from 2011 to the present

Expert Opinion on Therapeutic Patents

Volumn 25, Issue 1, 2015, Pages 49-68

  Yang, Yanyan ^a   Yu, Tao ^a   Lian, Yu Ji ^b   Ma, Rujun ^c   Yang, Sungjae ^c   Cho, Jae Youl ^c  

^a QINGDAO UNIVERSITY   (China)

^b LINYI UNIVERSITY   (China)

^c Sungkyunkwan University   (South Korea)

Author keywords

Efficacy and selectivity; Inducible nitric oxide synthase inhibitors; Inflammation; Neurodegenerative disorders; Nitric oxide synthase

Indexed keywords

ARGININE; ASTRAZENECA; BACTERIAL NITRIC OXIDE SYNTHASE; ENDOTHELIAL NITRIC OXIDE SYNTHASE; INDOLE DERIVATIVE; INDUCIBLE NITRIC OXIDE SYNTHASE; KALYPSYS; NEURONAL NITRIC OXIDE SYNTHASE; NITRIC OXIDE SYNTHASE; NITRIC OXIDE SYNTHASE INHIBITOR; NYCOMED; UNCLASSIFIED DRUG; ENZYME INHIBITOR;

ACUTE PANCREATITIS; ANGIOGENESIS; BINDING SITE; BIOLOGICAL FUNCTIONS; BLOOD VESSEL TONE; CIRCADIAN RHYTHM; ENZYME ACTIVITY; HEART MUSCLE ISCHEMIA; HUMAN; HYPERALGESIA; HYPERTENSION; INSULIN RELEASE; MEMORY; NERVE CELL; NERVE FIBER; NEUROPATHIC PAIN; PERISTALSIS; PROTEIN PROTEIN INTERACTION; REGULATORY MECHANISM; REPERFUSION INJURY; REVIEW; SIGNAL TRANSDUCTION; ANIMAL; ANTAGONISTS AND INHIBITORS; CHEMICAL STRUCTURE; CHEMISTRY; DRUG DESIGN; DRUG INDUSTRY; LEGISLATION AND JURISPRUDENCE; METABOLISM; PATENT; PROTEIN CONFORMATION; STRUCTURE ACTIVITY RELATION;

ANIMALS; DRUG DESIGN; DRUG INDUSTRY; ENZYME INHIBITORS; HUMANS; MOLECULAR STRUCTURE; NITRIC OXIDE SYNTHASE; PATENTS AS TOPIC; PROTEIN CONFORMATION; STRUCTURE-ACTIVITY RELATIONSHIP;

EID: 84919416940     PISSN: 13543776     EISSN: 17447674     Source Type: Journal    
DOI: 10.1517/13543776.2014.979154     Document Type: Review

References (87)

1. Palmer RM, Ferrige AG, Moncada S. Nitric oxide release accounts for the biological activity of endothelium-derived relaxing factor. Nature 1987;327:524-6
2. Hou YC, Janczuk A, Wang PG. Current trends in the development of nitric oxide donors. Curr Pharm Des 1999;5:417-41
3. Eckersten D, Henningsson R. Nitric oxide (NO)-production and regulation of insulin secretion in islets of freely fed and fasted mice. Regul Pept 2012;174:32-7
4. Folkerts G, van der Linde H, Verheyen AK, et al. Endogenous nitric oxide modulation of potassium-induced changes in guinea-pig airway tone. Br J Pharmacol 1995;115:1194-8
5. Yun HY, Dawson VL, Dawson TM. Neurobiology of nitric oxide. Crit Rev Neurobiol 1996;10:291-316
6. Murohara T, Asahara T, Silver M, et al. Nitric oxide synthase modulates angiogenesis in response to tissue ischemia. J Clin Invest 1998;101:2567-78
7. Hibbs JB Jr, Taintor RR, Vavrin Z. Macrophage cytotoxicity: role for Larginine deiminase and imino nitrogen oxidation to nitrite. Science 1987;235:473-6
8. Nagy G, Clark JM, Buzas EI, et al. Nitric oxide, chronic inflammation and autoimmunity. Immunol Lett 2007;111:1-5
9. Martin NI, Woodward JJ, Winter MB, et al. Design and synthesis of C5 methylated L-arginine analogues as active site probes for nitric oxide synthase. J Am Chem Soc 2007;129:12563-70
10. Knowles RG, Moncada S. Nitric oxide synthases in mammals. Biochem J 1994;298(Pt 2):249-58
11. Stuehr DJ. Mammalian nitric oxide synthases. Biochim Biophys Acta 1999;1411:217-30
12. Alderton WK, Cooper CE, Knowles RG. Nitric oxide synthases: structure, function and inhibition. Biochem J 2001;357:593-615
13. Joubert J, Malan SF. Novel nitric oxide synthase inhibitors: a patent review. Expert Opin Ther Pat 2011;21:537-60
14. Flinspach ML, Li H, Jamal J, et al. Structural basis for dipeptide amide isoform-selective inhibition of neuronal nitric oxide synthase. Nat Struct Mol Biol 2004;11:54-9
15. Li H, Poulos TL. Structure-function studies on nitric oxide synthases. J Inorg Biochem 2005;99:293-305
16. Gusarov I, Starodubtseva M, Wang ZQ, et al. Bacterial nitric-oxide synthases operate without a dedicated redox partner. J Biol Chem 2008;283:13140-7
17. Pant K, Crane BR. Nitrosyl-heme structures of Bacillus subtilis nitric oxide synthase have implications for understanding substrate oxidation. Biochemistry 2006;45:2537-44
18. Pant K, Bilwes AM, Adak S, et al. Structure of a nitric oxide synthase heme protein from Bacillus subtilis. Biochemistry 2002;41:11071-9
19. Salard I, Mercey E, Rekka E, et al. Analogies and surprising differences between recombinant nitric oxide synthase-like proteins from Staphylococcus aureus and Bacillus anthracis in their interactions with larginine analogs and iron ligands. J Inorg Biochem 2006;100:2024-33
20. Bredt DS, Snyder SH. Nitric oxide, a novel neuronal messenger. Neuron 1992;8:3-11
21. Pavesi E, Heldt SA, Fletcher ML. Neuronal nitric-oxide synthase deficiency impairs the long-term memory of olfactory fear learning and increases odor generalization. Learn Mem 2013;20:482-90
22. Game X, Rischmann P, Arnal JF, Malavaud B. [Nitric oxide pathway and female lower urinary tract. Physiological and pathophysiological role]. Prog Urol 2013;23:926-35
23. Zhang YH, Jin CZ, Jang JH, et al. Molecular mechanisms of neuronal nitric oxide synthase in cardiac function and pathophysiology. J Physiol 2014;592:3189-200
24. Rodebaugh J, Sekulic M, Davies W, et al. Neuronal nitric oxide synthase, nNOS, regulates renal hemodynamics in the postnatal developing piglet. Pediatr Res 2012;71:144-9
25. McLeod DS, Baba T, Bhutto IA, et al. Co-expression of endothelial and neuronal nitric oxide synthases in the developing vasculatures of the human fetal eye. Graefes Arch Clin Exp Ophthalmol 2012;250:839-48
26. Payandemehr B, Rahimian R, Gooshe M, et al. Nitric oxide mediates the anticonvulsant effects of thalidomide on pentylenetetrazole-induced clonic seizures in mice. Epilepsy Behav 2014;34:99-104
27. Lirk P, Hoffmann G, Rieder J. Inducible nitric oxide synthase-time for reappraisal. Curr Drug Targets Inflamm Allergy 2002;1:89-108
28. Qader SS, Ekelund M, Andersson R, et al. Acute pancreatitis, expression of inducible nitric oxide synthase and defective insulin secretion. Cell Tissue Res 2003;313:271-9
29. Smith CJ, Santhanam L, Bruning RS, et al. Upregulation of inducible nitric oxide synthase contributes to attenuated cutaneous vasodilation in essential hypertensive humans. Hypertension 2011;58:935-42
30. Niu S, Shingle DL, Garbarino-Pico E, et al. The circadian deadenylase Nocturnin is necessary for stabilization of the iNOS mRNA in mice. PLoS One 2011;6:e26954
31. Lange M, Hamahata A, Traber DL, et al. Effects of early neuronal and delayed inducible nitric oxide synthase blockade on cardiovascular, renal, and hepatic function in ovine sepsis. Anesthesiology 2010;113:1376-84
32. Chen TH, Liao FT, Yang YC, et al. Inhibition of inducible nitric oxide synthase ameliorates myocardial ischemia/reperfusion injury-induced acute renal injury. Transplant Proc 2014;46:1123-6
33. Alp BF, Malkoc E, Demirer Z, et al. Inhibition of inducible nitric oxide synthase prevents shock wave therapy induced renal injury. Ren Fail 2014;36:774-80
34. Camargo EA, Santana DG, Silva CI, et al. Inhibition of inducible nitric oxide synthase-derived nitric oxide as a therapeutical target for acute pancreatitis induced by secretory phospholipase A2. Eur J Pain 2014;18:691-700
35. Oliveira-Paula GH, Lacchini R, Tanus-Santos JE. Inducible nitric oxide synthase as a possible target in hypertension. Curr Drug Targets 2014;15:164-74
36. Nasadyuk C, Sklyarov A. Thymohexin exhibits cytoprotective effect in experimental gastric lesions in rats both through the inhibition of inducible nitric oxide synthase and reduction of oxidative mucosal damage. Regul Pept 2013;180:50-7
37. Ropelle ER, Pauli JR, Cintra DE, et al. Targeted disruption of inducible nitric oxide synthase protects against aging, Snitrosation, and insulin resistance in muscle of male mice. Diabetes 2013;62:466-70
38. Hong CW, Kim YM, Pyo H, et al. Involvement of inducible nitric oxide synthase in radiation-induced vascular endothelial damage. J Radiat Res 2013;54:1036-42
39. Najafi S, Payandemehr B, Tabrizian K, et al. The role of nitric oxide in the PKA inhibitor induced spatial memory deficits in rat: involvement of choline acetyltransferase. Eur J Pharmacol 2013;714:478-85
40. Liu Y, Feng Q. NOing the heart: role of nitric oxide synthase-3 in heart development. Differentiation 2012;84:54-61
41. Gusarov I, Nudler E. NO-mediated cytoprotection: instant adaptation to oxidative stress in bacteria. Proc Natl Acad Sci USA 2005;102:13855-60
42. Crane BR, Sudhamsu J, Patel BA. Bacterial nitric oxide synthases. Annu Rev Biochem 2010;79:445-70
43. Rosen GM, Tsai P, Weaver J, et al. The role of tetrahydrobiopterin in the regulation of neuronal nitric-oxide synthase-generated superoxide. J Biol Chem 2002;277:40275-80
44. Zhang L, Dawson VL, Dawson TM. Role of nitric oxide in Parkinson's disease. Pharmacol Ther 2006;109:33-41
45. Dorheim MA, Tracey WR, Pollock JS, et al. Nitric oxide synthase activity is elevated in brain microvessels in Alzheimer's disease. Biochem Biophys Res Commun 1994;205:659-65
46. Norris PJ, Faull RL, Emson PC. Neuronal nitric oxide synthase (nNOS) mRNA expression and NADPHdiaphorase staining in the frontal cortex, visual cortex and hippocampus of control and Alzheimer's disease brains. Brain Res Mol Brain Res 1996;41:36-49
47. Sims NR, Anderson MF. Mitochondrial contributions to tissue damage in stroke. Neurochem Int 2002;40:511-26
48. Calabrese V, Mancuso C, Calvani M, et al. Nitric oxide in the central nervous system: neuroprotection versus neurotoxicity. Nat Rev Neurosci 2007;8:766-75
49. Annedi SC, Ramnauth J, Maddaford SP, et al. Discovery of cis-N-(1-(4-(methylamino)cyclohexyl)indolin-6-yl) thiophene-2-carboximidamide: a 1,6-disubstituted indoline derivative as a highly selective inhibitor of human neuronal nitric oxide synthase (nNOS) without any cardiovascular liabilities. J Med Chem 2012;55:943-55.
50. Mladenova G, Annedi SC, Ramnauth J, et al. First-in-class, dual-action, 3,5-disubstituted indole derivatives having human nitric oxide synthase (nNOS) and norepinephrine reuptake inhibitory (NERI) activity for the treatment of neuropathic pain. J Med Chem 2012;55:3488-501.
51. Ramnauth J, Speed J, Maddaford SP, et al. Design, synthesis, and biological evaluation of 3,4-dihydroquinolin-2(1H)-one and 1,2,3,4-tetrahydroquinolinebased selective human neuronal nitric oxide synthase (nNOS) inhibitors. J Med Chem 2011;54:5562-75
52. Annedi SC, Maddaford SP, Ramnauth J, et al. 3,5-Disubstituted indole derivatives as selective human neuronal nitric oxide synthase (nNOS) inhibitors. Bioorg Med Chem Lett 2012;22:1980-4
53. Annedi SC, Maddaford SP, Mladenova G, et al. Discovery of N-(3-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-1H-indol-6-yl) thiophene-2-carboximidamide as a selective inhibitor of human neuronal nitric oxide synthase (nNOS) for the treatment of pain. J Med Chem 2011;54:7408-16
54. Maddaford S, Renton P, Speed J, et al. 1,6-Disubstituted indole derivatives as selective human neuronal nitric oxide synthase inhibitors. Bioorg Med Chem Lett 2011;21:5234-8
55. Renton P, Green B, Maddaford S, et al. NOpiates: novel dual action neuronal nitric oxide synthase inhibitors with muopioid agonist activity. ACS Med Chem Lett 2012;3:227-31
56. Huang H, Li H, Martasek P, et al. Structure-guided design of selective inhibitors of neuronal nitric oxide synthase. J Med Chem 2013;56:3024-32
57. Jing Q, Li H, Roman LJ, et al. An accessible chiral linker to enhance potency and selectivity of neuronal nitric oxide synthase inhibitors. ACS Med Chem Lett 2014;5:56-60
58. Kang S, Tang W, Li H, et al. Nitric oxide synthase inhibitors that interact with both heme propionate and tetrahydrobiopterin show high isoform selectivity. J Med Chem 2014;57:4382-96.
59. Delker SL, Ji H, Li H, et al. Unexpected binding modes of nitric oxide synthase inhibitors effective in the prevention of a cerebral palsy phenotype in an animal model. J Am Chem Soc 2010;132:5437-42
60. Ji H, Tan S, Igarashi J, et al. Selective neuronal nitric oxide synthase inhibitors and the prevention of cerebral palsy. Ann Neurol 2009;65:209-17
61. Li H, Xue F, Kraus JM II, et al. Cyclopropyl-and methyl-containing inhibitors of neuronal nitric oxide synthase. Bioorg Med Chem 2013;21:1333-43
62. Kroncke KD, Fehsel K, Kolb-Bachofen V. Inducible nitric oxide synthase in human diseases. Clin Exp Immunol 1998;113:147-56
63. Ma Q, Wang Z, Zhang M, et al. Targeting the L-arginine-nitric oxide pathway for cancer treatment. Curr Pharm Des 2010;16:392-410
64. Cheshire DR, Aberg A, Andersson GM, et al. The discovery of novel, potent and highly selective inhibitors of inducible nitric oxide synthase (iNOS). Bioorg Med Chem Lett 2011;21:2468-71
65. Gradler U, Fuchss T, Ulrich WR, et al. Novel nanomolar imidazo[4,5-b] pyridines as selective nitric oxide synthase (iNOS) inhibitors: SAR and structural insights. Bioorg Med Chem Lett 2011;21:4228-32
66. Schulz U, Grossmann A, Witetschek M, et al. Investigations on synthesis and structure elucidation of novel [1,2,4] triazolo[1,2-a]pyridazine-1-thiones and their inhibitory activity against inducible nitric oxide synthase. Bioorg Med Chem 2013;21:5518-31
67. Zamora R, Vodovotz Y, Billiar TR. Inducible nitric oxide synthase and inflammatory diseases. Mol Med 2000;6:347-73
68. Gahman TC, Herbert MR, Lang H, et al. Identification and SAR of selective inducible nitric oxide synthase (iNOS) dimerization inhibitors. Bioorg Med Chem Lett 2011;21:6888-94
69. Duron SG, Lindstrom A, Bonnefous C, et al. Heteroaromatic-aminomethyl quinolones: potent and selective iNOS inhibitors. Bioorg Med Chem Lett 2012;22:1237-41
70. Symons KT, Nguyen PM, Massari ME, et al. Pharmacological characterization of KLYP961, a dual inhibitor of inducible and neuronal nitric-oxide synthases. J Pharmacol Exp Ther 2011;336:468-78
71. Lee J, Kim H, Lee TG, et al. Anmindenols A and B, inducible nitric oxide synthase inhibitors from a marinederived streptomyces sp. J Nat Prod 2014;77:1528-31
72. Wu L, Wang X, Xu W, et al. The structure and pharmacological functions of coumarins and their derivatives. Curr Med Chem 2009;16:4236-60
73. Stefani HA, Gueogjan K, Manarin F, et al. Synthesis, biological evaluation and molecular docking studies of 3-(triazolyl)-coumarin derivatives: effect on inducible nitric oxide synthase. Eur J Med Chem 2012;58:117-27
74. Suaifan GA, Shehadehh M, Al-Ijel H, et al. Extensive ligand-based modeling and in silico screening reveal nanomolar inducible nitric oxide synthase (iNOS) inhibitors. J Mol Graph Model 2012;37:1-26
75. Ignarro LJ. Nitric oxide as a unique signaling molecule in the vascular system: a historical overview. J Physiol Pharmacol 2002;53:503-14
76. Vallance P, Leiper J. Blocking NO synthesis: how, where and why Nat Rev Drug Discov 2002;1:939-50
77. Poulos TL, Li H. Structural basis for isoform-selective inhibition in nitric oxide synthase. Acc Chem Res 2013;46:390-8
78. Gusarov I, Gautier L, Smolentseva O, et al. Bacterial nitric oxide extends the lifespan of C. elegans. Cell 2013;152:818-30
79. Gusarov I, Shatalin K, Starodubtseva M, et al. Endogenous nitric oxide protects bacteria against a wide spectrum of antibiotics. Science 2009;325:1380-4
80. Holden JK, Li H, Jing Q, et al. Structural and biological studies on bacterial nitric oxide synthase inhibitors. Proc Natl Acad Sci USA 2013;110:18127-31.
81. Blottner D, Grozdanovic Z, Gossrau R. Histochemistry of nitric oxide synthase in the nervous system. Histochem J 1995;27:785-811
82. Tatchum-Talom R, Schulz R, McNeill JR, et al. Upregulation of neuronal nitric oxide synthase in skeletal muscle by swim training. Am J Physiol Heart Circ Physiol 2000;279:H1757-66
83. Burger DE, Lu X, Lei M, et al. Neuronal nitric oxide synthase protects against myocardial infarction-induced ventricular arrhythmia and mortality in mice. Circulation 2009;120:1345-54
84. Niu X, Watts VL, Cingolani OH, et al. Cardioprotective effect of beta-3 adrenergic receptor agonism: role of neuronal nitric oxide synthase. J Am Coll Cardiol 2012;59:1979-87
85. Chakravortty D, Hensel M. Inducible nitric oxide synthase and control of intracellular bacterial pathogens. Microbes Infect 2003;5:621-7
86. Karpuzoglu E, Ahmed SA. Estrogen regulation of nitric oxide and inducible nitric oxide synthase (iNOS) in immune cells: implications for immunity, autoimmune diseases, and apoptosis. Nitric Oxide 2006;15:177-86
87. Pampusch MS, Bennaars AM, Harsch S, et al. Inducible nitric oxide synthase expression in porcine immune cells. Vet Immunol Immunopathol 1998;61:279-89