Novel series of potent, nonsteroidal, selective androgen receptor modulators based on 7H-[1,4]oxazino[3,2-g]quinolin-7-ones

Journal of Medicinal Chemistry

Volumn 50, Issue 10, 2007, Pages 2486-2496

  Higuchi, Robert I ^a   Arienti, Kristen L ^a,b   López, Francisco J ^a   Mani, Neelakhanda S ^a,b   Mais, Dale E ^a   Caferro, Thomas R ^a   Long, Yun Oliver ^a   Jones, Todd K ^a,b   Edwards, James P ^a,b   Zhi, Lin ^a   Schrader, William T ^a,c   Negro Vilar, Andrés ^a   Marschke, Keith B ^a  

^a LIGAND PHARMACEUTICALS INC   (United States)

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

^c NATIONAL INSTITUTE OF ENVIRONMENTAL HEALTH SCIENCES   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

1 (2,2 DIMETHYLPROPYL) 1,2,3,6 TETRAHYDRO 9 (TRIFLUOROMETHYL) 7H [1,4]OXAZINO[3,2 G]QUINOLIN 7 ONE; 1 BENZYL 1,2,3,6 TETRAHYDRO 9 (TRIFLUOROMETHYL) 7H [1,4]OXAZINO[3,2 G]QUINOLIN 7 ONE; 1 CYCLOPROPYLMETHYL 1,2,3,6 TETRAHYDRO 9 (TRIFLUOROMETHYL) 7H [1,4]OXAZINO[3,2 G]QUINOLIN 7 ONE; 1 ETHYL 1,2,3,6 TETRAHYDRO 9 (TRIFLUOROMETHYL) 7H [1,4]OXAZINO[3,2 G]QUINOLIN 7 ONE; 1,2,3,4,4A,5 HEXAHYDRO 11 (TRIFLUOROMETHYL) PYRIDO[1,2:4,5]OXAZINO[3,2 G]QUINOLIN 9(8H) ONE; 1,2,3,6 TETRAHYDRO 1 (2,2,2 TRIFLUOROETHYL) 9 (TRIFLUOROMETHYL) 7H [1,4]OXAZINO[3,2 G]QUINOLIN 7 ONE; 1,2,3,6 TETRAHYDRO 1 ISOBUTYL 9 (TRIFLUOROMETHYL) 7H [1,4]OXAZINO[3,2 G]QUINOLIN 7 ONE; 1,2,3,6 TETRAHYDRO 1 METHYL 9 (TRIFLUOROMETHYL) 7H [1,4]OXAZINO[3,2 G]QUINOLIN 7 ONE; 1,2,3,6 TETRAHYDRO 1 PROPYL 9 (TRIFLUOROMETHYL) 7H [1,4]OXAZINO[3,2 G]QUINOLIN 7 ONE; 1,2,3,6 TETRAHYDRO 1,3 DIMETHYL 9 (TRIFLUOROMETHYL) 7H [1,4]OXAZINO[3,2 G]QUINOLIN 7 ONE; 1,2,3,6 TETRAHYDRO 2 ISOBUTYL 1 (2,2,2 TRIFLUOROETHYL) 9 (TRIFLUOROMETHYL) 7H [1,4]OXAZINO[3,2 G]QUINOLIN 7 ONE; 1,2,3,6 TETRAHYDRO 2 ISOPROPYL 1 (2,2,2 TRIFLUOROETHYL) 9 (TRIFLUOROMETHYL) 7H [1,4]OXAZINO[3,2 G]QUINOLIN 7 ONE; 1,2,3,6 TETRAHYDRO 2 METHYL (2,2,2 TRIFLUOROETHYL) 9 (TRIFLUOROMETHYL) 7H [1,4]OXAZINO[3,2 G]QUINOLIN 7 ONE; 1,2,3,6 TETRAHYDRO 3 METHYL 1 (2,2,2 TRIFLUOROETHYL) 9 (TRIFLUOROMETHYL) 7H [1,4]OXAZINO[3,2 G]QUINOLIN 7 ONE; 1,2,3,6 TETRAHYDRO 9 (TRIFLUOROMETHYL) 7H [1,4]OXAZINO[3,2 G]QUINOLIN 7 ONE; 1,3 DIETHYL 1,2,3,6 TETRAHYDRO 9 (TRIFLUOROMETHYL) 7H [1,4]OXAZINO[3,2 G]QUINOLIN 7 ONE; 2 ETHYL 1,2,3,6 TETRAHYDRO 1 (2,2,2 TRIFLUOROMETHYL) 9 (TRIFLUOROMETHYL) 7H [1,4]OXAZINO[3,2 G]QUINOLIN 7 ONE; 2,3,3A,4 TETRAHYDRO 10 (TRIFLUOROMETHYL) 1H PYRROLO[1,2:4,5][1,4]OXAZINO[3,2 G]QUINOLIN 8(7H) ONE; 3 ETHYL 1,2,3,6 TETRAHYDRO 1 (2,2,2 TRIFLUOROMETHYL) 9 (TRIFLUOROMETHYL) 7H [1,4]OXAZINO[3,2 G]QUINOLIN 7 ONE; 3 ETHYL 1,2,3,6 TETRAHYDRO 1 METHYL 9 (TRIFLUOROMETHYL) 7H [1,4]OXAZINO[3,2 G]QUINOLIN 7 ONE; QUINOLINE DERIVATIVE; UNCLASSIFIED DRUG;

ANDROGEN THERAPY; ANIMAL EXPERIMENT; ARTICLE; BINDING ASSAY; CONTROLLED STUDY; DRUG EFFICACY; DRUG PROTEIN BINDING; DRUG SYNTHESIS; HUMAN; HUMAN CELL; MALE; MUSCLE; NONHUMAN; PROSTATE; RAT; TRANSCRIPTION INITIATION;

ANABOLIC AGENTS; ANIMALS; BINDING, COMPETITIVE; CELL LINE, TUMOR; HUMANS; MALE; MUSCLE, SKELETAL; ORGAN SIZE; OXAZINES; PROSTATE; QUINOLONES; RADIOLIGAND ASSAY; RATS; RATS, SPRAGUE-DAWLEY; RECEPTORS, ANDROGEN; STEREOISOMERISM; STRUCTURE-ACTIVITY RELATIONSHIP; TRANS-ACTIVATION (GENETICS);

EID: 34249081708     PISSN: 00222623     EISSN: None     Source Type: Journal    
DOI: 10.1021/jm061329j     Document Type: Article

References (32)

1. Rosen, J.; Day, A.; Jones, T. K.; Jones, E. T.; Nadzan, A. M.; Stein, R. B. Intracellular receptors and signal transducers and activators of transcription superfamilies: Novel targets for small-molecule drug discovery. J. Med. Chem. 1995, 38, 4855-4874.
2. Bagatell, C. J; Bremner, W. J. Androgens in men - Uses and abuses. N. Engl. J. Med. 1996, 334, 707-714.
3. (a) Bhasin, S.; Storer, T. W.; Berman, N.; Yarasheski, K. E.; Clevenger, B.; Phillips, J.; Lee, W. P.; Bunnel, T. J.; Casaburi, R. Testosterone replacement increases fat-free mass and muscle size in hypogonadal men. J. Clin. Endocrinol. Metab. 1997, 82, 407-413.
4. (b) Handelsman, D. J.; Liu, P. Y. Andropause: Invention, prevention, rejuvenation. Trends Endocrinol. Metab. 2005, 16, 39-45.
5. (c) Bhasin, S.; Woodhouse, L.; Casaburi, R.; Singh, A. B.; Mac, R. P.; Lee, M.; Yarasheski, K. E.; Sinha-Hikim, I.; Dzekov, J.; Magliano, L.; Storer, T. W. Older men are as responsive as young men to the anabolic effects of graded doses of testosterone on skeletal muscle. J. Clin. Endocrinol. Metab. 2005, 90, 678-688.
6. (d) Zacharin, M. R.; Pua, J.; Kanumakala, S. Bone mineral density outcomes following long-term treatment with subcutaneous testosterone pellet implants in male hypogonadism. Clin. Endocrinol. 2003, 58, 691-695.
7. Negro-Vilar, A.; Selective androgen receptor modulators (SARMs): A novel approach to androgen therapy for the new millennium. J. Clin. Endocrinol. Metab. 1999, 84, 3459-3462.
8. Liu, P. Y.; Handelsman, D. J. Androgen Therapy in Non-Gonadal Disease. In Testosterone Action, Deficiency, Substitution, 3rd edition; Nieschlag, E., Behre, H. M., Eds.; Cambridge University Press: New York, 2004; pp 446-472.
9. Marhefka, C. A.; Gao, W.; Chung, W.; Kim, J.; He, Y.; Yin, D.; Bohl, C.; Dalton, J. T.; Miller, D. D. Design, synthesis, and biological characterization of metabolically stable selective androgen receptor modulators. J. Med. Chem. 2004, 47, 993-998.
10. (b) Bohl, C. E.; Chang, C.; Mohler, M. L.; Chen, J.; Miller, D. D.; Swaan, P. W.; Dalton, J. T. A ligand-based approach to identify quantitative structure-activity relationships for the androgen receptor, (c) Gao, W.; Bohl, C. E.; Dalton, J. T. Chemistry and structural biology of androgen receptor. Chem. Rev. 2005, 105, 3352-3370.
11. (a) Sun, C.; Robl, J. A.; Wang, T. C.; Huang, Y.; Kuhns, J. E.; Lupisella, J. A.; Beehler, B. C.; Golla, R.; Sleph, P. G.; Seethala, R.; Fura, A.; Krystek, S. R.; An, Y.; Malley, M. F.; Sack, J. S.; Salvati, M. E.; Grover, G. J.; Ostrowski, J.; Hamann, L. G. Discovery of potent, orally-active, and muscle-selective androgen receptor modulators based on an N-aryl- hydroxybicyclohydantoin scaffold. J. Med. Chem. 2006, 49, 7596-7599.
12. (b) Zhang, X.; Allan, G. F.; Sbriscia, T.; Linton, O.; Lundeen, S. G.; Sui, Z. Synthesis and SAR of novel hydantoin derivatives as selective androgen receptor modulators. Bioorg. Med. Chem. Lett. 2006, 16, 5763-5766.
13. (c) Lanter, J. C.; Fiordeliso, J. J.; Allan, G. F.; Musto, A.; Hahn, D. W.; Sui, Z. Bioorg. Med. Chem. Lett. 2006, 16, 5646-5649.
14. (d) Hanada, K.; Furuya, K;, Yamamoto, N.; Nejishima, H.; Ichikawa, K.; Nakamura, T.; Miyakawa, M.; Amano, S.; Sumita, Y.; Oguro, N. Bone anabolic effects of S-40503, a novel nonsteroidal selective androgen receptor modulator (SARM), in rat models of osteoporosis. Biol. Pharm. Bull. 2003, 26, 1563-1569.
15. (a) Hamann, L. G.; Mani, N. S.; Davis, R. L.; Wang, X.-N.; Marschke, K. B.; Jones, T. K. Discovery of a potent, orally active nonsteroidal androgen receptor agonist: 4-Ethyl-1,2,3,4-tetrahydro-6-(trifluoromethyl)-8-pyridono[5,6- g]quinoline (LG121071). J. Med. Chem. 1999, 42, 210-212.
16. (b) Higuchi, R. I.; Edwards, J. P.; Caferro, T. R.; Ringgenberg, J. D.; Kong, J. W.; Hamann, L. G.; Arienti, K. L.; Davis, R. L.; Farmer, L. J.; Jones, T. K. 4-Alkyl- and 3,4-dialkyl-1,2,3,4-tetrahydro-8-pyridono[5,6-g]quinolines: Potent, nonsteroidal androgen receptor agonists. Bioorg. Med. Chem. Lett. 1999, 9, 1335-1340.
17. (c) Edwards, J. P.; Higuchi, R. I.; Winn, D. T.; Pooley, C. L. F.; Caferro, T. R.; Hamann, L. G.; Zhi, L.; Marschke, K. B.; Goldman, M. E.; Jones, T. K. Nonsteroidal androgen receptor agonists based on 4-(trifluoromethyl)- 2H-pyrano[3,2-g]quinolin-2-one. Bioorg. Med. Chem. Lett. 1999, 9, 1003-1008.
18. (d) Zhi, L.; Tegley, C. M.; Marschke, K. B.; Jones, T. K. Switching androgen receptor antagonists to agonist by modifying C-ring substituents on piperidino[3,2-g]quinolinone. Bioorg. Med. Chem. Lett. 1999, 9, 1009-1012.
19. Hamann, L. G.; Higuchi, R. I.; Zhi, L.; Edwards, J. P.; Wang, X.-N.; Marschke, K. B.; Kong, J. W.; Farmer, L. J.; Jones, T. K. Synthesis and biological activity of a novel series of nonsteroidal, peripherally selective androgen receptor antagonists derived from 1,2-dihydropyridono[5,6-g]quinolines. J. Med. Chem. 1998, 41, 623-639.
20. Unpublished results from our laboratories.
21. (a) Van Oeveren, A.; Motamedi, M.; Mani, N. S.; Marschke, K. B.; Lopez, F. J.; Schrader, W. T.; Negro-Vilar, A.; Zhi, L. Discovery of 6-N,N-bis(2,2,2-triflouroethyl)amino-4-trifluoromethylquinolin-2(1 H)-one as a novel selective androgen receptor modulator. J. Med. Chem. 2006, 49, 6143-6146.
22. (b) Van Oeveren, A.; Motamedi, M.; Martinborough, E.; Zhao, S.; Shen, Y.; West, S.; Chang, W.; Kallel, A.; Marschke, K. B.; López, F. J.; Negro-Vilar, A.; Zhi, L. Novel selective androgen receptor modulators: SAR studies on 6-bisalkylamino-2-quinolinones. Bioorg. Med. Chem. Lett. 2007, 17, 1527-1531.
23. Shridhar, D. R.; Jogibhukta, M.; Krishnan, V. S. H. A general and convenient synthesis of 2H-1,4-benzoxazin-3(4H)-ones. Org. Prep. Proced. Int. 1982, 14, 195-197.
24. Matsumoto, Y.; Tsuzuki, R.; Matsuhisa, A.; Takayama, K.; Yoden, T.; Uchida, W.; Asano, M.; Fujita, S.; Yanagisawa, I.; Fujikura, T. Novel potassium channel activators: Synthesis and structure-activity relationship studies of 3,4-dihydro-2H-1,4-benzoxazine derivatives. Chem. Pharm. Bull. 1996, 44, 103-114.
25. (a) Kelly, T. R.; Field, J. A.; Li, Q. Synthesis of diazaquinomycin A and B: The first double Knorr cyclization. Tetrahedron Lett. 1988, 29, 3545-3546.
26. (b) Forbis, R. M.; Rinehart, K. L. Nybomycin. VII. Preparative routes to nybomycin and deoxynybomycin. J. Am. Chem. Soc. 1973, 95, 5003-5013.
27. (a) From chiral epoxides: Xie, L. J. A facile synthesis of chiral 3-alkyl-3,4-dihydro-2H-1,4-benzoxazine derivatives. Chin. Chem. Lett. 1995, 6, 857-860.
28. (b) Baker's yeast reduction: Kang, S. B.; Ahn, E. J.; Kim, Y. A facile synthesis of (S)-(-)-7,8-difluoro-3,4-dihydro-3-methyl-2H-1,4- benzoxazine by zinc chloride assisted Mitsunobu cyclization reaction. Tetrahedron Lett. 1996, 37, 9317-9320.
29. Hall, R. E.; Birrell, S. N.; Tilley, W. D.; Sutherland, R. L. MDA-MB-453, an androgen-responsive human breast carcinoma cell line with high-level androgen receptor expression. Eur. J. Cancer 1994, 30, 484-490.
30. Herschberger, L. G.; Shipley, E. G.; Meyer, R. K. Myotropic activity of 19-nortestosterone and other steroids determined by modified levator ani muscle method. Proc. Soc. Exp. Biol. Med. 1953, 83, 175-180.
31. 50) of an enzymatic reaction. Biochem. Pharmacol. 1973, 22, 3099-3108.
32. Pathirana, C.; Stein, R. B.; Berger, T. S.; Fenical, W.; Ianiro, T.; Mais, D.; Torres, A.; Goldman, M. E.; Nonsteroidal human progesterone receptor modulators from the marine alga cymopolia barbata. Mol. Pharmacol. 1995, 47, 630-635.