Design, synthesis, and activity of 2-imidazol-1-ylpyrimidine derived inducible nitric oxide synthase dimerization inhibitors

Journal of Medicinal Chemistry

Volumn 50, Issue 6, 2007, Pages 1146-1157

  Davey, David D ^a   Adler, Marc ^a   Arnaiz, Damian ^a   Eagen, Keith ^a   Erickson, Shawn ^a   Guilford, William ^a   Kenrick, Margaret ^a   Morrissey, Michael M ^a   Ohlmeyer, Mike ^b   Pan, Gonghua ^a   Paradkar, Vidyadhar M ^b   Parkinson, John ^a   Polokoff, Mark ^a   Saionz, Kurt ^b   Santos, Cecile ^a   Subramanyam, Babu ^a   Vergona, Ron ^a   Wei, Robert G ^a   Whitlow, Marc ^a   Ye, Bin ^a   Zhao, Zuchun ^a   Devlin, James J ^a   Phillips, Gary ^a   more..

^a BAYER AG   (Germany)

^b PHARMACOPEIA INC   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

2 (IMIDAZOL 1 YL)PYRIMIDINE DERIVATIVE; IMIDAZOLE DERIVATIVE; INDUCIBLE NITRIC OXIDE SYNTHASE; N [2 (1,3 BENZODIOXOL 5 YL)ETHYL] 1 [2 (1H IMIDAZOL 1 YL) 6 METHYL 4 PYRIMIDINYL] 2 PYRROLIDINE CARBOXAMIDE; NITRIC OXIDE SYNTHASE INHIBITOR; PYRIMIDINE DERIVATIVE; UNCLASSIFIED DRUG;

ADJUVANT ARTHRITIS; ANIMAL CELL; ANIMAL EXPERIMENT; ANIMAL MODEL; ARTICLE; COMBINATORIAL CHEMISTRY; CONTROLLED STUDY; CRYSTAL STRUCTURE; DIMERIZATION; DRUG ACTIVITY; DRUG DESIGN; DRUG DOSE COMPARISON; DRUG MECHANISM; DRUG STRUCTURE; DRUG SYNTHESIS; MALE; NONHUMAN; PROTEIN PROTEIN INTERACTION; RAT; STRUCTURE ACTIVITY RELATION;

ANIMALS; ANTI-INFLAMMATORY AGENTS, NON-STEROIDAL; ARTHRITIS, EXPERIMENTAL; BENZODIOXOLES; CELL LINE; CERCOPITHECUS AETHIOPS; CRYSTALLOGRAPHY, X-RAY; DIMERIZATION; IMIDAZOLES; MALE; MODELS, MOLECULAR; NITRIC OXIDE SYNTHASE TYPE II; PYRIMIDINES; RATS; RATS, INBRED LEW;

EID: 33947699769     PISSN: 00222623     EISSN: None     Source Type: Journal    
DOI: 10.1021/jm061319i     Document Type: Article

References (23)

1. Parkinson, J. F.; Devlin, J. J.; Phillips, G. B. Nitric oxide synthase inhibitors. Endothelial Cell Res. Ser. 1999, 505-521.
2. Salerno, I.; Sorrenti, V.; Di Giacomo, C.; Romeo, G.; Siracusa, M. A. Progress in the development of selective nitric oxide synthase inhibitors, Curr. Pharm. Des. 2002, 8, 177-200.
3. Proskuryakov, S. V.; Konoplyannikov, A. G.; Skvortsov, V. G.; Mandrugin, A. A.; Fedoseev, V. M. Structure and activity of NO synthase inhibitors specific to the L-arginine binding site. Biochemistry (Moscow) 2005, 70, 8-23.
4. Wolff, D. J.; Gribin, B. J. Interferon-gamma-inducible murine macrophage nitric oxide synthase: studies on the mechanism of inhibition by imidazole agents. Arch. Biochem. Biophys. 1994, 311, 293-299.
5. Chabin, R. M.; McCauley, E.; Calaycay, J. R.; Kelly, T. M.; MacNaul, K. L.; Wolfe, G. C.; Hutchinson, N. I.; Madhusudanaraju, S.; Schmidt, J. A.; Kozarich, J. W. Wong, K. K. Active-site structure analysis of recombinant human inducible nitric oxide synthase using imidazole. Biochemistry 1996, 35, 9567-75.
6. Hoelscher, P.; Rehwinkel, H.; Burton, G.; Phillips, G.; Parkinson, J. New and Known Phenyl and Pyridyl Imidazole Derivatives Are Nitrogen Monoxide Synthase Inhibitors Used To Treat Neurodegenerative, Autoimmune, Inflammatory, and Circulatory Disease. WO 9715555, 1997.
7. Ohlmeyer, M. H. J.; Swanson, R. N.; Dillard, L. W.; Reader, J. C.; Asouline, G.; Kobayashi, R.; Wigler, M.; Still, W. C. Complex synthetic chemical libraries indexed with molecular tags. Proc. Natl. Acad. Sci. U.S.A. 1993, 90, 10922-26.
8. McMillan, K.; Adler, M.; Auld, D. S.; Baldwin, J. J.; Blasko, E.; Browne, L. J.; Chelsky, D.; Davey, D.; Dolle, R. E.; Eagan, K. A.; Erickson, S.; Feldman, R. I.; Glaser, C.; Mallari, C.; Morrissey, M. M.; Ohlmeyer, M. H. J.; Pan, G.; Parkinson, J. F.; Phillips, G. B.; Polokolff, M. A.; Sigal, N. A.; Vergona, R.; Whitlow, M.; Young, T.; Devlin, J. J. Allosteric inhibitors of inducible nitric oxide synthase dimerization discovered via combinatorial chemistry. Proc. Natl. Acad. Sci. U.S.A. 2000, 97, 1506-1511.
9. Sennequier, N.; Wolan, D.; Stuehr, D. J. Antifungal imidazoles block assembly of inducible NO synthase into an active dimer J. Biol. Chem. 1999, 274, 930-938.
10. Ohtsuka, M.; Konno, F.; Honda, H.; Oikawa, T.; Ishikawa, M.; Iwase, N.; Isomae, K.; Ishii, F.; Hemmi, H.; Sato, S. PPA250 [3-(2,4-Difluorophenyl)-6-{2- [4-(1H-imidazol-1-ylmethyl)phenoxy]ethoxy}-2-phenylpyridine], a novel orally effective inhibitor of the dimerization of inducible nitric-oxide synthase, exhibits an anti-inflammatory effect in animal models of chronic arthritis. J. Pharmacol. Exp. Ther. 2002, 303, 52-57.
11. Chida, N.; Hirasawa, Y.; Ohkawa, T.; Ishii, Y.; Sudo, U.; Tamura, K.; Mutoh, S. Pharmacological profile of FR260330, a novel orally active inducible nitric oxide synthase inhibitor. Eur. J. Pharmacol. 2005, 509, 71-6.
12. Blasko, E.; Glaser, C. B.; Devlin, J. J.; Xia, W.; Feldman, R. I.; Polokoff, M. A.; Phillips, G. B.; Whitlow, M.; Auld, D. S.; McMillan, K.; Ghosh, S.; Stuehr, D. J.; Parkinson, J. F. Mechanistic studies with potent and selective inducible nitric-oxide synthase dimerization inhibitors. J. Biol. Chem. 2002, 277, 295-302.
13. Afonso, A.; Baldwin, J. J.; Doll, R. J.; Li, G.; Mallams, A. K.; Njoroge, F. G.; Rane, D. F.; Reader, J. C.; Rossman, R. R. Preparation of Heterocyclic Tricyclic Compounds Useful for Inhibition of g-Protein Function and for Treatment of Cell Proliferative Diseases. WO9631478, 1996.
14. Van den Branden, S.; Compernolle, F.; Hoorneaert, G. J. Synthesis of lactam and ketone precursors of 2,7-substituted octahydropyrrolo-[1,2-a] pyrazines and octahydro-2H-pyrido[1,2-a]pyrazines. J. Chem. Soc., Perkin Trans. 1 1992, 1035-1042.
15. 50 > 10 μM in one of the selectivity assays, 10 μM was used in the ratio calculation.
16. Bredt, D. S.; Snyder, S. H. Isolation of NOS, a calmodulin-requiring enzyme. Proc. Natl. Acad. Sci. U.S.A. 1990, 87, 682-685.
17. The structure of the 4-methoxyphenethylamide analogue (instead of the piperonylamide of 19d) was determined by X-ray crystallography, and the corresponding stereochemistry of 19d is inferred (PDB entry 2ORP).
18. Li, H.; Raman, C. S.; Glaser, C. B.; Blasko, E.; Young, T. A.; Parkinson, J. F.; Whitlow, M.; Poulos, T. L. Crystal structures of zinc-free and -bound heme domain of human iNOS. J. Biol. Chem. 1999, 274, 21276-21284.
19. Arnaiz, D. O.; Baldwin, J. J.; Davey, D. D.; Devlin, J. J.; Dolle, R. E., III; Erickson, S. D.; McMillan, K.; Morrissey, M. M.; Ohlmeyer, M. H. J.; Pan, G.; Paradkar, V. M.; Parkinson, J.; Phillips, G. B.; Ye, B.; Zhao, Z. N-Heterocyclic Derivatives as NOS Inhibitors. U.S. Patent 6,849,739, 2005.
20. Johnson, A. L.; Kauer, J. C.; Sharma, D. C.; Dorfman, R. I. Synthesis of 1-arylimidazoles, a new class of steroid hydroxylation inhibitors. J. Med. Chem. 1969, 12, 1024-1028.
21. Lambert, P. H.; Vaultier, M.; Carrie, R. Application of the intramolecular aza-Wittig reaction to the synthesis of vinylogous urethanes and amides. J. Org. Chem. 1985, 50, 5352-5356.
22. Pearson, C. M. Development of arthritis, periarthritis and periostitis in rats given adjuvants. Proc. Soc. Exp. Biol. Med. 1956, 91, 95-101.
23. Ackerman, N. R.; Rooks, W. H.; Shott, L.; Genant, H.; Maloney, P.; West, E. Effects of naproxen on connective tissue changes in the adjuvant arthritic rat. Arthritis Rheum. 1979, 22, 1365-1374.