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

Journal of Medicinal Chemistry

Volumn 55, Issue 2, 2012, Pages 943-955

  Annedi, Subhash C ^a   Ramnauth, Jailall ^a   Maddaford, Shawn P ^a   Renton, Paul ^a   Rakhit, Suman ^a   Mladenova, Gabriela ^a   Dove, Peter ^a   Silverman, Sarah ^a   Andrews, John S ^a   Felice, Milena D ^b   Porreca, Frank ^b  

^a NeurAxon Inc   (Canada)

^b UNIVERSITY OF ARIZONA COLLEGE OF MEDICINE   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

ARGININE; ENDOTHELIAL NITRIC OXIDE SYNTHASE; INDOLE DERIVATIVE; ISOENZYME; N (1 CYCLOHEXYLINDOLIN 6 YL)THIOPHENE 2 CARBOXIMIDAMIDE; N [1 (PIPERIDIN 4 YL)INDOLIN 6 YL]THIOPHENE 2 CARBOXIMIDAMIDE; N [1 (PYRROLIDIN 3 YL)INDOLIN 6 YL]THIOPHENE 2 CARBOXIMIDAMIDE; N [1 (TETRAHYDRO 2H PYRAN 4 YL)INDOLIN 6 YL]THIOPHENE 2 CARBOXIMIDAMIDE; N [1 (TETRAHYDRO 2H THIOPYRAN 4 YL)INDOLIN 6 YL]THIOPHENE 2 CARBOXIMIDAMIDE; N [1 [2 (2 HYDROXYETHYLAMINO)ETHYL]INDOLIN 6 YL]THIOPHENE 2 CARBOXIMIDAMIDE; N [1 [2 (3 HYDROXYPYRROLIDIN 1 YL)ETHYL]INDOLIN 6 YL]THIOPHENE 2 CARBOXIMIDAMIDE; N [1 [4 (METHYLAMINO)CYCLOHEXYL]INDOLIN 6 YL]THIOPHENE 2 CARBOXIMIDAMIDE; N [5 FLUORO 1 (PIPERIDIN 4 YL)INDOLIN 6 YL]THIOPHENE 2 CARBOXIMIDAMIDE; N [5 FLUORO 1 [4 (METHYLAMINO)CYCLOHEXYL]INDOLIN 6 YL]THIOPHENE 2 CARBOXIMIDAMIDE; NEURONAL NITRIC OXIDE SYNTHASE; NITRIC OXIDE; NITRIC OXIDE SYNTHASE INHIBITOR; NORADRENALIN TRANSPORTER; OXYGENASE INHIBITOR; POTASSIUM CHANNEL HERG; QUINOLINE DERIVATIVE; UNCLASSIFIED DRUG;

ALKYLATION; ALLODYNIA; ANIMAL EXPERIMENT; ANIMAL MODEL; ANIMAL TISSUE; ARTICLE; CARDIOVASCULAR DISEASE; CONTROLLED STUDY; DRUG DESIGN; DRUG IDENTIFICATION; DRUG POTENCY; DRUG SAFETY; DRUG SELECTIVITY; DRUG SYNTHESIS; DRUG TARGETING; ENZYME INHIBITION; HIGH THROUGHPUT SCREENING; HUMAN; HUMAN CELL; HUMAN TISSUE; HYPERALGESIA; IC 50; IN VITRO STUDY; IN VIVO STUDY; LIPOPHILICITY; NERVE LIGATION; NEUROPATHIC PAIN; NEUROPROTECTION; NONHUMAN; PROTEIN FUNCTION; QT PROLONGATION; RAT; SPINAL NERVE; STRUCTURE ACTIVITY RELATION; THERMAL INJURY; VASCULAR RESISTANCE; VASOCONSTRICTION; VASODILATATION;

ANALGESICS; ANIMALS; ARTERIES; CARDIOVASCULAR SYSTEM; ETHER-A-GO-GO POTASSIUM CHANNELS; HEK293 CELLS; HIGH-THROUGHPUT SCREENING ASSAYS; HUMANS; INDOLES; NEURALGIA; NITRIC OXIDE SYNTHASE TYPE I; NITRIC OXIDE SYNTHASE TYPE II; NITRIC OXIDE SYNTHASE TYPE III; PATCH-CLAMP TECHNIQUES; RATS; STEREOISOMERISM; STRUCTURE-ACTIVITY RELATIONSHIP; THIOPHENES; VASCULAR RESISTANCE; VASOCONSTRICTION;

EID: 84856380860     PISSN: 00222623     EISSN: 15204804     Source Type: Journal    
DOI: 10.1021/jm201564u     Document Type: Article

References (36)

1. J. Med. Chem. 2011, 54, 5562 - 5575
2. Mustafa, A. K.; Gadalla, M. M.; Synder, S. H. Signaling by gasotransmitters Sci. Signaling 2009, 2, 1-8
3. Moncada, S.; Palmer, R. M. J.; Higgs, E. A. Nitric Oxide: Physiology, Pathophysiology, and Pharmacology Pharmacol. Rev. 1991, 43, 109-142
4. Alderton, W. K.; Cooper, C. E.; Knowles, R. G. Nitric oxide synthases: structure, function and inhibition Biochem. J. 2001, 357, 593-615 (Pubitemid 32735142)
5. Stuehr, D. J. Structure-function aspects in the nitric oxide synthases Annu. Rev. Pharmacol. Toxicol. 1997, 37, 339-359 (Pubitemid 27238880)
6. Vallance, P.; Leiper, J. Blocking NO synthesis: how, where and why? Nature Rev. Drug Discovery 2002, 1, 939-950 (Pubitemid 37361600)
7. Calabrese, V.; Mancuso, C.; Calvani, M.; Rizzarelli, E.; Butterfield, A. D.; Stella, A. M. G. Nitric oxide in the central nervous system: neuroprotection versus neurotoxicity Nature Rev. Neurosci. 2007, 8, 766-775 (Pubitemid 47462116)
8. Miclescu, A.; Gordh, T. Nitric oxide and pain: "something old, something new" Acta Anaesthesiol. Scand. 2009, 53, 1107-1120
9. Huang, P. L.; Huang, Z.; Mashimo, H.; Bloch, K. D.; Moskowitz, M. A.; Bevan, J. A.; Fishman, M. C. Hypertension in mice lacking the gene for endothelial nitric oxide synthase Nature 1995, 377, 239-242
10. Lassen, H. L.; Iverson, H. K.; Olesen, J. A dose-response study of nitric oxide synthase inhibition in different vascular beds in man Eur. J. Clin. Pharmacol. 2003, 59, 499-505 (Pubitemid 37363561)
11. 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 and references within.
12. Erdal, E. P.; Litzinger, E. A.; Seo, J.; Zhu, Y.; Ji, H.; Silverman, R. B. Selective neuronal nitric oxide synthase inhibitors Curr. Top. Med. Chem. 2005, 5, 603-624 (Pubitemid 41179723)
13. Tinker, A. C.; Wallace, A. V. Selective inhibitors of inducible nitric oxide synthase: potential agents for the treatment of inflammatory diseases? Curr. Top. Med. Chem. 2006, 6, 77-92
14. Silverman, R. B. Design of selective neuronal nitric oxide synthase inhibitors for the prevention and treatment of neurodegenerative diseases Acc. Chem. Res. 2009, 42, 439-451
15. Patman, J.; Bhardwaj, N.; Ramnauth, J.; Annedi, S. C.; Renton, P.; Maddaford, S. P.; Rakhit, S.; Andrews, J. S. Novel 2-aminobenzothiazoles as selective neuronal nitric oxide synthase inhibitors Bioorg. Med. Chem. Lett. 2007, 17, 2540-2544 (Pubitemid 46509840)
16. 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
17. 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
18. Annedi, S. C.; Maddaford, S. P.; Mladenova, G.; Ramnauth, J.; Rakhit, S.; Andrews, J. S.; Lee, D. K. H.; Zhang, D.; Porreca, F.; Bunton, D.; Christie, L. Discovery of N -(3-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-1 H -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, 7408-7416
19. 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. H.; Felice, M. D.; Porreca, F. Design, synthesis and biological evaluation of 3,4-dihydroquinolin-2(1 H)-one and 1,2,3,4-tetrahydroquiniline-based selective human neuronal nitric oxide synthase (nNOS) inhibitors J. Med. Chem. 2011, 54, 5562-5575
20. O'Neill, M. J.; Murray, T. K.; McCarty, D. R.; Hicks, C. A.; Dell, C. P.; Patrick, K. E.; Ward, M. A.; Osborne, D. J.; Wiernicki, T. R.; Roman, C. R.; Lodge, D.; Fleisch, J. H.; Singh, J. ARL 17477, a selective nitric oxide synthase inhibitor, with neuroprotective effects in animal models of global and focal cerebral ischaemia Brain Res. 2000, 871, 234-244 (Pubitemid 30433875)
21. Leeson, P. D.; Springthorpe, B. The influence of druglike concepts on decision-making in medicinal chemistry Nature Rev. Drug Discovery 2007, 6, 881-890 (Pubitemid 350042396)
22. Waring, M. J. Lipophilicity in drug discovery Expert Opin. Drug Discovery 2010, 5, 235-248
23. Abdel-Magid, A. F.; Carson, K. G.; Harris, B. D.; Maryanoff, C. A.; Shah, R. D. Reductive amination of aldehydes and ketones with sodium triacetoxyborohydride. Studies on direct and indirect reductive amination procedures J. Org. Chem. 1996, 61, 3849-3862 (Pubitemid 126532674)
24. Bercot-Vatteroni, M. Thiophene derivatives of possible therapeutic interest Ann. Chim. 1962, 7, 303-337
25. Hasimbegovic, V.; Slätt, J.; Bergman., J.; Janosik, T. The synthesis of some 3-acylindoles revisited J. Heterocycl. Chem. 2007, 44, 1213-1217 (Pubitemid 350196745)
26. Chamberlain, S.; Deanda, F. J.; Gerding, R.; Hasegawa, M.; Kuntz, K.; Shotwell, J. B.; Wilson, J.; Lei, H. J.; Miyazaki, Y.; Nishigaki, N.; Patnaik, S.; Redman, A.; Stevens, K.; Yang, B. 2-[(2-{Phenylamino}-1 H -pyrrolo[2,3- d ]pyrimidin-4-yl)amino]benzamide derivatives as IGF-1r inhibitors for the treatment of cancer. WO 2009020990 A1, 2009.
27. Huang, X.; Buchwald, S. New ammonia equivalents for the Pd-catalyzed amination of aryl halides Org. Lett. 2001, 3, 3417-3419 (Pubitemid 33625374)
28. 1H chemical shifts of alcohols, diols and inositols in solution, a conformational and solvation investigation Magn. Reson. Chem. 2005, 43, 611-624 (Pubitemid 40992717)
29. Leeson, P. D.; St-Gallay, S. A. The influence of the "organizational factor" on compound quality in drug discovery Nature Rev. Drug Discovery 2011, 10, 749-765 and references within.
30. Jaroch, S.; Rehwinkel, H.; Hölscher, P.; Sülzle, D.; Burton, G.; Hillmann, M.; McDonald, F. M.; Miklautz, H. Fluorinated dihydroquinolines as potent n -NOS inhibitors Bioorg. Med. Chem. Lett. 2004, 14, 743-746 (Pubitemid 38114864)
31. Kim, S. H.; Chung, J. M. An experimental model for peripheral neuropathy produced by segmental spinal nerve ligation in the rat Pain 1992, 50, 355-363
32. Fermini, B.; Fossa, A. A. The impact of drug-induced QT interval prolongation on drug discovery and development Nature Rev. 2003, 2, 439-447 (Pubitemid 37361725)
33. Zhou, Z.; Gong, Q.; Ye, B.; Fan, Z.; Makielski, J. C.; Robertson, G. A.; January, C. T. Properties of HERG channels stably expressed in HEK 293 cells studied at physiological temperature Biophys. J. 1998, 74, 230-241 (Pubitemid 28041752)
34. + channel blockade: current knowledge and strategies for the early prediction during drug development Med. Res. Rev. 2005, 25, 133-166 (Pubitemid 40299844)
35. Jamieson, C.; Moir, E. M.; Rankovic, Z.; Wilshart, G. Medicinal chemistry of hERG optimizations: Highlights and hung-ups J. Med. Chem. 2006, 49, 5029-5046 (Pubitemid 44260200)
36. Cerep; http://www.cerep.fr/.