Discovery of dual inducible/neuronal nitric oxide synthase (iNOS/nNOS) inhibitor development candidate 4-((2-cyclobutyl-1 H-imidazo[4,5- b ]pyrazin-1-yl)methyl)-7,8-difluoroquinolin-2(1 H)-one (KD7332) Part 2: Identification of a novel, potent, and selective series of benzimidazole- quinolinone iNOS/nNOS dimerization inhibitors that are orally active in pain models

Journal of Medicinal Chemistry

Volumn 53, Issue 21, 2010, Pages 7739-7755

  Payne, Joseph E ^a,d   Bonnefous, Céline ^a,b   Symons, Kent T ^a,g   Nguyen, Phan M ^a   Sablad, Marciano ^a,c   Rozenkrants, Natasha ^a,c   Zhang, Yan ^a,c   Wang, Li ^a,e   Yazdani, Nahid ^a,f   Shiau, Andrew K ^a,i   Noble, Stewart A ^a   Rix, Peter ^a,b   Rao, Tadimeti S ^a,c   Hassig, Christian A ^a,h   Smith, Nicholas D ^a,b  

^a Kalypsys Inc   (United States)

^b Aragon Pharmaceuticals   (United States)

^c JOHNSON AND JOHNSON PHARMACEUTICAL RESEARCH AND DEVELOPMENT   (United States)

^d Biomedical Group   (United States)

^e Bio Quant Inc   (United States)

^f Helicon Foundation   (United States)

^g DART NEUROSCIENCE LLC   (United States)

^h Sanford Burnham Medical Research Institute   (United States)

ⁱ UNIVERSITY OF CALIFORNIA   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

4 [(2 CYCLOBUTYL 1H IMIDAZO[4,5 B]PYRAZIN 1 YL)METHYL] 7,8 DIFLUOROQUINOLIN 2(1H) ONE; 4 [[2 CYCLOBUTYL 1H BENZO[D]IMIDAZOL 1 YL]METHYL] 7,8 DIFLUOROQUINOLIN 2(1H) ONE; 4 [[2 CYCLOHEXYL 1H BENZO[D]IMIDAZOL 1 YL]METHYL] 7,8 DIFLUOROQUINOLIN 2(1H) ONE; 4 [[2 CYCLOPENTYL 1H BENZO[D]IMIDAZOL 1 YL]METHYL] 7,8 DIFLUOROQUINOLIN 2(1H) ONE; 4 [[2 CYCLOPROPYL 1H BENZO[D]IMIDAZOL 1 YL]METHYL] 7,8 DIFLUOROQUINOLIN 2(1H) ONE; 4 [[2 TERT BUTYL 1H BENZO[D]IMIDAZOL 1 YL]METHYL] 7,8 DIFLUOROQUINOLIN 2(1H) ONE; 4,7 IMIDAZOPYRAZINE; 7,8 DIFLUORO 4 [[2 (1 METHYL 1H IMIDAZOL 5 YL) 1H BENZO[D] IMIDAZOL 1 YL]METHYL]QUINOLIN 2(1H) ONE; 7,8 DIFLUORO 4 [[2 (3 METHYLPYRIDIN 4 YL) 1H BENZO[D]IMIDAZOL 1 YL]METHYL]QUINOLIN 2(1H) ONE; 7,8 DIFLUORO 4 [[2 (4 METHYLPYRIDIN 3 YL) 1H BENZO[D]IMIDAZOL 1 YL]METHYL]QUINOLIN 2(1H) ONE; 7,8 DIFLUORO 4 [[2 (4 METHYLTHIAZOL 5 YL) 1H BENZO[D]IMIDAZOL 1 YL]METHYL]QUINOLIN 2(1H) ONE; 7,8 DIFLUORO 4 [[2 (PYRIDIN 2 YL) 1H BENZO[D]IMIDAZOL 1 YL]METHYL]QUINOLIN 2(1H) ONE; 7,8 DIFLUORO 4 [[2 (PYRIDIN 3 YL) 1H BENZO[D]IMIDAZOL 1 YL] METHYL]QUINOLIN 2(1H) ONE; 7,8 DIFLUORO 4 [[2 (PYRIDIN 4 YL) 1H BENZO[D]IMIDAZOL 1 YL]METHYL]QUINOLIN 2(1H) ONE; 7,8 DIFLUORO 4 [[2 (THIAZOL 5 YL) 1H BENZO[D]IMIDAZOL 1 YL]METHYL]QUINOLIN 2(1H) ONE; 7,8 DIFLUORO 4 [[2 ETHYL 1H BENZO[D]IMIDAZOL 1 YL]METHYL] QUINOLIN 2(1H) ONE; 7,8 DIFLUORO 4 [[2 ISOBUTYL 1H BENZO[D]IMIDAZOL 1 YL]METHYL] QUINOLIN 2(1H) ONE; 7,8 DIFLUORO 4 [[2 ISOPROPYL 1H BENZO[D]IMIDAZOL 1 YL]METHYL] QUINOLIN 2(1H) ONE; 7,8 DIFLUORO 4 [[2 PROPYL 1H BENZO[D]IMIDAZOL 1 YL]METHYL] QUINOLIN 2(1H) ONE; 8 FLUORO 4 [[2 (4 METHYLTHIAZOL 5 YL) 1H BENZO[D]IMIDAZOL 1 YL]METHYL]QUINOLIN 2(1H) ONE; AMIDE; ANTINOCICEPTIVE AGENT; ARGININE; BENZIMIDAZOLE; CYTOCHROME P450; KD 7332; LIPOPOLYSACCHARIDE; NITRIC OXIDE; NITRIC OXIDE SYNTHASE; PYRAZINE DERIVATIVE; QUINOLONE DERIVATIVE; UNCLASSIFIED DRUG;

ANIMAL EXPERIMENT; AREA UNDER THE CURVE; ARTICLE; CATALYSIS; CONFORMATION; DIMERIZATION; DRUG DEVELOPMENT; DRUG STRUCTURE; HUMAN; HUMAN CELL; MAXIMUM PLASMA CONCENTRATION; MOUSE; NEUROPATHIC PAIN; NOCICEPTION; NONHUMAN; STRUCTURE ACTIVITY RELATION; SUBSTITUTION REACTION;

ADMINISTRATION, ORAL; ANALGESICS; ANIMALS; CELL LINE; DRUG TOLERANCE; FLUOROQUINOLONES; HUMANS; MICE; MICROSOMES, LIVER; NITRIC OXIDE SYNTHASE TYPE I; NITRIC OXIDE SYNTHASE TYPE II; PAIN; PAIN MEASUREMENT; PERIPHERAL NERVOUS SYSTEM DISEASES; PROTEIN MULTIMERIZATION; PYRAZINES; ROTAROD PERFORMANCE TEST; STRUCTURE-ACTIVITY RELATIONSHIP;

EID: 78149269550     PISSN: 00222623     EISSN: 15204804     Source Type: Journal    
DOI: 10.1021/jm100828n     Document Type: Article

References (31)

1. Alderton, W. K.; Cooper, C. E.; Knowles, R. G. Nitric oxide synthases: structure, function and inhibition Biochem. J. 2001, 357, 593-615
2. Levy, D.; Zochodne, D. W. NO Pain: Potential Roles of Nitric Oxide in Neuropathic Pain Pain Pract. 2004, 4 (1) 11-18
3. Vallance, P.; Leiper, J. Blocking NO Synthesis: How, Where, and Why? Nature Rev. Drug Discovery 2002, 1, 939-950
4. Wu, J.; Fang, L.; Lin, Q.; Willis, W. D. Nitric oxide synthase in spinal cord central sensitization following intradermal injection of capsaicin Pain 2001, 94, 47-58
5. Guan, Y.; Yaster, M.; Raja, S. N.; Tao, Y. Genetic knockout and pharmacologic inhibition of neuronal nitric oxide synthase attenuate nerve injury-induced mechanical hypersensitivity in mice Mol. Pain 2007, 3, 29
6. Paige, J. S.; Jaffrey, S. R. Pharmacologic Manipulation of Nitric Oxide Signaling: Targeting NOS Dimerization and Protein-Protein Interactions Curr. Top. Med. Chem. 2007, 7, 97-114
7. Alderton, W. K.; Angell, A. D. R.; Craig, C.; Dawson, J.; Garvey, E.; Moncada, S.; Monkhouse, J.; Rees, D.; Russell, L. J.; Russell, R. J.; Schwartz, S.; Waslidge, N.; Knowles, R. G. GW274150 and GW273629 are potent and highly selective inhibitors of inducible nitric oxide synthase in vitro and in vivo Br. J. Pharmacol. 2005, 145, 301-312
8. Alba, D. A; Clayton, N. M.; Collins, S. D.; Colthup, P.; Chessell, I.; Knowles, R. G. GW274150, a novel and highly selective inhibitor of the inducible isoform of nitric oxide synthase (iNOS), shows analgesic effects in rat models of inflammatory and neuropathic pain Pain 2006, 120, 170-181
9. Edwards, R. M.; Stack, E. J.; Trizna, W. Interaction of l -Arginine Analogs With l -Arginine Uptake in Rat Renal Brush Border Membrane Vesicles J. Pharmacol. Exp. Ther. 1998, 285, 1019-1022
10. LaBuda, C. J.; Koblish, M.; Tuthill, P.; Dolle, R. E.; Little, P. J. Antinociceptive activity of the selective iNOS inhibitor AR-C102222 in rodent models of inflammatory, neuropathic and post-operative pain Eur. J. Pain 2005, 10 (6) 505-512
11. Tinker, A. C.; Beaton, H. G.; Boughton-Smith, N.; Cook, T. R.; Cooper, S. L.; Fraser-Rae, L.; Hallam, K.; Hamley, P.; McInally, T.; Nicholls, D. J.; Pimm, A. D.; Wallace, A. V. 1,2-Dihydro-4-quinazolinamines: Potent, Highly Selective Inhibitors of Inducible Nitric Oxide Synthase Which Show Antiinflammatory Activity in Vivo J. Med. Chem. 2003, 46 (6) 913-916
12. Davey, D. D.; Adler, M.; Arnaiz, D.; Eagen, K.; Erickson, S.; Guilford, W.; Kenrick, M.; Morrissey, M. M.; Ohlmeyer, M.; Pan, G.; Paradkar, V. M.; Parkinson, J.; Polokoff, M.; Saionz, K.; Santos, C.; Subramanyam, B.; Vergona, R.; Wei, R. G.; Whitlow, M.; Ye, B.; Zhao, Z. S.; Devlin, J. J.; Phillips, G. Design, Synthesis, and Activity of 2-Imidazol-1-ylpyrimidine Derived Inducible Nitric Oxide Synthase Dimerization Inhibitors J. Med. Chem. 2007, 50 (6) 1146-1157 (Pubitemid 46496315)
13. 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
14. Nason, D. M.; Heck, S. D.; Bodenstein, M. S.; Lowe, J. A., III; Nelson, R. B.; Liston, D. R.; Nolan, C. E.; Lanyon, L. F.; Ward, K. M.; Volkmann, R. A. Substituted 6-phenyl-pyridin-2-ylamines: selective and potent inhibitors of neuronal nitric oxide synthase Bioorg. Med. Chem. Lett. 2004, 14, 4511-4514
15. Bonnefous, C.; Payne, J. E.; Roppe, J.; Zhang, H.; Chen, X.; Symons, K. T.; Nguyen, P. H.; Sablad, M.; Rozenkrants, N.; Zhang, Y.; Wang, L.; Severance, D.; Walsh, J. P.; Yazdani, N.; Shiau, A. K.; Noble, S. A.; Rix, P.; Rao, T. S.; Hassig, C. A.; Smith, N. D. Discovery of Inducible Nitric Oxide Synthase (iNOS) Inhibitor Development Candidate KD7332, Part 1: Identification of a Novel, Potent, and Selective Series of Quinolinone iNOS Dimerization Inhibitors That Are Orally Active in Rodent Pain Models J. Med. Chem. 2009, 52 (9) 3047-3062
16. As disclosed previously, modification of the quinolinone portion of 8 did not lead to an improvement in rodent pharmacokinetics. See ref 11.
17. Choi, H. Y.; Chi, D. Y. Nonselective Bromination-Selective Debromination Strategy: Selective Bromination of Unsymmetrical Ketones on Singly Activated Carbon against Doubly Activated Carbon Org. Lett. 2003, 5 (4) 411-414
18. 2 atmosphere (see preparation of compound 47).
19. 6: δ = 5.53 (s, 1H)), the structure of which was confirmed by X-ray Diffraction. Similar chemical shifts of the quinolinone C3 hydrogen were observed with analogues 33 - 41, 44 - 50.
20. Elimination rate under conditions of combined phase I oxidation and phase II glucoronide conjugation.
21. Alkylation of the symmetrical benzimidazole core can lead only to the desired compound 42 and the region-isomer 43. In contrast, alkylation of the nonsymmetrical benzimidazoles to give compounds 36-41 can lead to three products.
22. Wang, L. X.; Wang, Z. J. Animal and cellular models of chronic pain Adv. Drug Delivery Rev. 2003, 55, 949-965
23. Dubuisson, D.; Dennis, S. G. The Formalin Test: A Quantitative Study of the Analgesic Effects of Morphine, Meperidine, and Brain Stem Stimulation in Rats and Cats Pain 1977, 4, 161-174
24. The brain penetration of 42 was determined in the rat by microdialysis and was found to be 2% of the plasma concentration (see ref 22).
25. Symons, K. T.; Nguyen, P. H.; Massari, M. E.; Anzola, J. V.; Staszewski1, L. M.; Wang, L.; Yazdani, N.; Dorow, S.; Muhammad, J.; Sablad, M.; Rozenkrants, N.; Bonefous, C.; Payne, J. E.; Rix, P.; Shiau, A. K.; Noble, S. A.; Smith, N. D.; Hassig, C. A.; Zhang, Z.; Rao, T. S. J. Pharmacol. Exp. Ther., 2010, in press.
26. De Laeter, J. R. Atomic Weights of the Elements Pure Appl. Chem. 1991, 63 (7) 975-90
27. Singh, M. P.; Bathini, Y.; Lown, J. W. Site Selective Alkoxymethylation of Imidazo[4,5- b ]pyridines: Structural Analysis by High Field NMR Methods Heterocycles 1993, 36 (5) 971-985
28. See Supporting Information for NOE traces and for compound numbering.
29. Misko, T. P.; Schilling, R. J.; Salvemini, D.; Moore, W. M.; Currie, M. G. A fluorometric assay for the measurement of nitrite in biological samples Anal. Biochem. 1993, 214, 11-16
30. 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
31. Dunham, N. W.; Miya, T. S. A note on a simple apparatus for detecting neurological deficit in rats and mice J. Am. Pharm. Assoc. 1957, 46, 208-209