Recent advances toward improving the bioavailability of neuronal nitric oxide synthase inhibitors

Current Topics in Medicinal Chemistry

Volumn 13, Issue 6 7, 2013, Pages 803-812

  Huang, He ^a   Silverman, Richard B ^a  

^a NORTHWESTERN UNIVERSITY   (United States)

Author keywords

2 aminopyridine; Bioavailability; Inhibitor; Isoform selectivity; Neuronal nitric oxide synthase; Thiophene 2 carboximidamide

Indexed keywords

2 AMINOPYRIDINE DERIVATIVE; NITRIC OXIDE SYNTHASE INHIBITOR; THIOPHENE DERIVATIVE;

ARTICLE; CRYSTAL STRUCTURE; DRUG BIOAVAILABILITY; DRUG CONFORMATION; HYDROGEN BOND; LIPOPHILICITY; NONHUMAN; STRUCTURE ACTIVITY RELATION;

EID: 84878811267     PISSN: 15680266     EISSN: 18734294     Source Type: Journal    
DOI: 10.2174/1568026611313070003     Document Type: Article

References (44)

1. Alderton, W.K.; Cooper, C.E.; Knowles, R.G.: Nitric oxide synthases: Structure, function and inhibition. Biochem. J. 2001, 357, 593-615.
2. Vallance, P.; Leiper, J.: Blocking NO synthesis: How, where and why? Nat. Rev. Drug Discov. 2002, 1, 939-950.
3. Rosen, G.M.; Tsai, P.; Pou, S.: Mechanism of free-radical generation by nitric oxide synthase. Chem Rev. 2002, 102, 1191-1199.
4. Olesen, J.: Nitric oxide-related drug targets in headache. Neurotherapeutics 2010, 7, 183-190.
5. Villanueva, C.; Giulivi, C.: Subcellular and cellular locations of nitric oxide synthase isoforms as determinants of health and disease. Free Radical Bio. Med. 2010, 49, 307-316.
6. Aquilano, K.; Baldelli, S.; Rotilio, G.; Ciriolo, M.R.: Role of nitric oxide synthases in Parkinson's disease: A review on the antioxidant and anti-inflammatory activity of polyphenols. Neurochem. Res. 2008, 33, 2416-2426.
7. Masic, L.P.: Arginine mimetic structures in biologically active antagonists and inhibitors. Curr. Med. Chem. 2006, 13, 3627-3648.
8. Oess, S.; Icking, A.; Fulton, D.; Govers, R.; Muller-Esterl, W.: Subcellular targeting and trafficking of nitric oxide synthases. Bio-chem. J. 2006, 396, 401-409.
9. Silverman, R.B.: Design of selective neuronal nitric oxide synthase inhibitors for the prevention and treatment of neurodegenerative diseases. Accounts Chem. Res. 2009, 42, 439-451.
10. Maddaford, S.; Annedi, S.C.; Ramnauth, J.; Rakhit, S.: Advancements in the development of nitric oxide synthase inhibitors. Annu. Rep. Med. Chem. 2009, 44, 27-50.
11. Hesslinger, C.; Strub, A.; Boer, R.; Ulrich, W.R.; Lehner, M.D.; Braun, C.: Inhibition of inducible nitric oxide synthase in respiratory diseases. Biochem. Soc. Trans. 2009, 37, 886-891.
12. Kanwar, J.R.; Kanwar, R.K.; Burrow, H.; Baratchi, S.: Recent advances on the roles of NO in cancer and chronic inflammatory disorders. Curr. Med. Chem. 2009, 16, 2373-2394.
13. Granik, V.G.; Grigor'ev, N.A.: Nitric oxide synthase inhibitors: Biology and chemistry. Russ. Chem. Bull. 2002, 51, 1973-1995.
14. Auvin, S.; Auguet, M.; Navet, E.; Harnett, J.J.; Viossat, I.; Schulz, J.; Bigg, D.; Chabrier, P.E.: Novel inhibitors of neuronal nitric oxide synthase with potent antioxidant properties. Bioorg. Med. Chem. Lett. 2003, 13, 209-212.
15. Beaton, H.; Boughton-Smith, N.; Hamley, P.; Ghelani, A.; Nicholls, D.J.; Tinker, A.C.; Wallace, A.V.: Thienopyridines: Nitric oxide synthase inhibitors with potent in vivo activity. Bioorg. Med. Chem. Lett. 2001, 11, 1027-1030.
16. Ueda, S.; Terauchi, H.; Yano, A.; Ido, M.; Matsumoto, M.; Kawasaki, M.: 4,5-disubstituted-1,3-oxazolidin-2-imine derivatives: A new class of orally bioavailable nitric oxide synthase inhibitor. Bioorg. Med. Chem. Lett. 2004, 14, 313-316.
17. Collins, J.L.; Shearer, B.G.; Oplinger, J.A.; Lee, S.L.; Garvey, E.P.; Salter, M.; Duffy, C.; Burnette, T.C.; Furfine, E.S.: N-Phenylamidines as selective inhibitors of human neuronal nitric oxide synthase: Structure-activity studies and demonstration of in vivo activity. J. Med. Chem. 1998, 41, 2858-2871.
18. Aoki, S.; Ye, Y.; Higuchi, K.; Takashima, A.; Tanaka, Y.; Kita-gawa, I.; Kobayashi, M.: Novel neuronal nitric oxide synthase (nNOS) selective inhibitor, aplysinopsin-type indole alkaloid, from marine sponge hyrtios erecta. Chem. Pharm. Bull. 2001, 49, 1372-1374.
19. Palumbo, A.; d'Ischia, M.; Cioffi, F.A.: 2-Thiouracil is a selective inhibitor of neuronal nitric oxide synthase antagonising tetrahydro-biopterin-dependent enzyme activation and dimerisation. FEBS Lett. 2000, 485, 109-112.
20. Ji, H.; Stanton, B.Z.; Igarashi, J.; Li, H.; Martasek, P.; Roman, L.J.; Poulos, T.L.; Silverman, R.B.: Minimal pharmacophoric elements and fragment hopping, an approach directed at molecular diversity and isozyme selectivity. Design of selective neuronal nitric oxide synthase inhibitors. J. Am. Chem. Soc. 2008, 130, 3900-3914.
21. Ji, H.; Tan, S.; Igarashi, J.; Li, H.; Derrick, M.; Martasek, P.; Roman, L.J.; Vasquez-Vivar, J.; Poulos, T.L.; Silverman, R.B.: Selective neuronal nitric oxide synthase inhibitors and the prevention of cerebral palsy. Ann. Neurol. 2009, 65, 209-217.
22. Delker, S.L.; Ji, H.; Li, H.; Jamal, J.; Fang, J.; Xue, F.; Silverman, R.B.; Poulos, T.L.: Unexpected binding modes of nitric oxide syn-thase inhibitors effective in the prevention of a cerebral palsy phenotype in an animal model. J. Am. Chem. Soc. 2010, 132, 5437-5442.
23. Ji, H.; Delker, S.L.; Li, H.Y.; Martasek, P.; Roman, L.J.; Poulos, T.L.; Silverman, R.B.: Exploration of the active site of neuronal nitric oxide synthase by the design and synthesis of pyrrolidi-nomethyl 2-aminopyridine derivatives. J. Med. Chem. 2010, 53, 7804-7824.
24. Hodgetts, K.J.; Combs, K.J.; Elder, A.M.; Harriman, G.C.: The role of fluorine in the discovery and optimization of cns agents: Modulation of drug-like properties. Ann. Rep. Med. Chem. 2010, 45, 429-448.
25. Xue, F.; Fang, J.; Lewis, W.W.; Martasek, P.; Roman, L.J.; Silver-man, R.B.: Potent and selective neuronal nitric oxide synthase inhibitors with improved cellular permeability. Bioorg. Med. Chem. Lett. 2010, 20, 554-557.
26. Xue, F.; Li, H.; Delker, S.L.; Fang, J.; Martasek, P.; Roman, L.J.; Poulos, T.L.; Silverman, R.B.: Potent, highly selective, and orally bioavailable gem-difluorinated monocationic inhibitors of neuronal nitric oxide synthase. J. Am. Chem. Soc. 2010, 132, 14229-14238.
27. Kuhn, B.; Mohr, P.; Stahl, M.: Intramolecular hydrogen bonding in medicinal chemistry. J. Med. Chem. 2010, 53, 2601-2611.
28. Jansen Labby, K.; Xue, F.; Kraus, J.M.; Ji, H.; Mataka, J.; Li, H.; Martasek, P.; Roman, L.J.; Poulos, T.L.; Silverman R.B.: Intramolecular hydrogen bonding: A potential strategy for more bioavailable inhibitors of neuronal nitric oxide synthase. Bioorg. Med. Chem. 2012, 20, 2435-2443.
29. Xue, F.; Huang, J.; Ji, H.; Fang, J.; Li, H.; Martasek, P.; Roman, L.J.; Poulos, T.L.; Silverman, R.B.: Structure-based design, synthesis, and biological evaluation of lipophilic-tailed monocationic inhibitors of neuronal nitric oxide synthase. Bioorg. Med. Chem. 2010, 18, 6526-6537.
30. Huang, H.; Ji, H.; Li, H.; Jing, Q.; Jansen Labby, K.; Martasek, P.; Roman, L.J.; Poulos, T.L.; Silverman, R.B.: Selective monoca-tionic inhibitors of neuronal nitric oxide synthase. Binding mode insights from molecular dynamics simulations. J. Am. Chem. Soc. 2012, 134, 11559-11572.
31. Xue, F.; Fang, J.; Delker, S.L.; Li, H.; Martasek, P.; Roman, L.J.; Poulos, T.L.; Silverman, R.B.: Symmetric double-headed amino-pyridines, a novel strategy for potent and membrane-permeable inhibitors of neuronal nitric oxide synthase. J. Med. Chem. 2011, 54, 2039-2048.
32. Delker, S.L.; Xue, F.; Li, H.; Jamal, J.; Silverman, R.B.; Poulos, T.L.: Role of zinc in isoform-selective inhibitor binding to neuronal nitric oxide synthase. Biochem. 2010, 49, 10803-10810.
33. Reif, D.W.; McCarthy, D.J.; Cregan, E.; Macdonald, J.E.: Discovery and development of neuronal nitric oxide synthase inhibitors. Free Radical Bio. Med. 2000, 28, 1470-1477.
34. Fedorov, R.; Vasan, R.; Ghosh, D.K.; Schlichting, I.: Structures of nitric oxide synthase isoforms complexed with the inhibitor AR-R17477 suggest a rational basis for specificity and inhibitor design. Proc. Natl. Acad. Sci. USA 2004, 101, 5892-5897.
35. Liang, G.; Neuenschwander, K.; Chen, X.; Wei, L.; Munson, R.; Francisco, G.; Scotese, A.; Shutske, G.; Black, M.; Sarhan, S.; Jiang, J.; Morize, I.; Vaz, R.J.: Structure-based design, synthesis, and profiling of potent and selective neuronal nitric oxide synthase (nNOS) inhibitors with an amidinothiophene hydroxypiperidine scaffold. MedChemComm 2011, 2, 201-205.
36. Ramnauth, J.; Speed, J.; Maddaford, S.P.; Dove, P.; Annedi, S.C.; Renton, P.; Rakhit, S.; Andrews, J.; Silverman, S.; Mladenova, G.; Zinghini, S.; Nair, S.; Catalano, C.; Lee, D.K.; De Felice, M.; Por-reca, F.: Design, synthesis, and biological evaluation of 3,4-dihydroquinolin-2(1H)-one and 1,2,3,4-tetrahydroquinoline-based selective human neuronal nitric oxide synthase (nNOS) inhibitors. J. Med. Chem. 2011, 54, 5562-5575.
37. Ramnauth, J.; Renton, P.; Dove, P.; Annedi, S.C.; Speed, J.; Sil-verman, S.; Mladenova, G.; Maddaford, S.P.; Zinghini, S.; Rakhit, S.; Andrews, J.; Lee, D.K.; Zhang, D.; Porreca, F.: 1,2,3,4-Tetrahydroquinoline-based selective human neuronal nitric oxide synthase (nNOS) inhibitors: Lead optimization studies resulting in the identification of n-(1-(2-(methylamino)ethyl)-1,2,3,4-tetrahydroquinolin-6-yl)thiophene-2-carboximi damide as a pre-clinical development candidate. J. Med. Chem. 2012, 55, 2882-2893.
38. Annedi, S.C.; Ramnauth, J.; Cossette, M.; Maddaford, S.P.; Dove, P.; Rakhit, S.; Andrews, J.S.; Porreca, F.: Novel, druglike 1,7-disubstituted 2,3,4,5-tetrahydro-1H-benzo[b]azepine-based selective inhibitors of human neuronal nitric oxide synthase (nNOS). Bioorg. Med. Chem. Lett. 2012, 22, 2510-2513.
39. Renton, P.; Speed, J.; Maddaford, S.; Annedi, S.C.; Ramnauth, J.; Rakhit, S.; Andrews, J.: 1,5-Disubstituted indole derivatives as selective human neuronal nitric oxide synthase inhibitors. Bioorg. Med. Chem. Lett. 2011, 21, 5301-5304.
40. Annedi, S.C.; Maddaford, S.P.; Mladenova, G.; Ramnauth, J.; Rakhit, S.; Andrews, J.S.; Lee, D.K.H.; Zhang, D.Q.; Porreca, F.; Bunton, D.; Christie, L.: Discovery of N-(3-(1-methyl-1,2,3,6- tetrahydropyridin-4-yl)-1h-indol-6-yl) thiophene-2-carboximi- damide as a selective inhibitor of human neuronal nitric oxide synthase (nNOS) for the treatment of pain. J. Med. Chem. 2011, 54, 7408-7416.
41. Mladenova, G.; Annedi, S.C.; Ramnauth, J.; Maddaford, S.P.; Rakhit, S.; Andrews, J.S.; Zhang, D.Q.; Porreca, F.: 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, 3488-3501.
42. Maddaford, S.; Renton, P.; Speed, J.; Annedi, S.C.; Ramnauth, J.; Rakhit, S.; Andrews, J.; Mladenova, G.; Majuta, L.; Porreca, F.: 1,6-Disubstituted indole derivatives as selective human neuronal nitric oxide synthase inhibitors. Bioorg. Med. Chem. Lett. 2011, 21, 5234-5238.
43. Annedi, S.C.; Maddaford, S.P.; Ramnauth, J.; Renton, P.; Speed, J.; Rakhit, S.; Andrews, J.S.; Porreca, F.: 3,5-Disubstituted indole derivatives as selective human neuronal nitric oxide synthase (nNOS) inhibitors. Bioorg. Med. Chem. Lett. 2012, 22, 1980-1984.
44. Annedi, S.C.; Ramnauth, J.; Maddaford, S.P.; Renton, P.; Rakhit, S.; Mladenova, G.; Dove, P.; Silverman, S.; Andrews, J.S.; Felice, M.D.; Porreca, F.: Discovery of cis-N-(1-(4-(methylamino) cyclo- hexyl)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 cardio vascular liabilities. J. Med. Chem. 2012, 55, 943-955.