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) [3]

Journal of Medicinal Chemistry

Volumn 42, Issue 2, 1999, Pages 210-212

  Hamann, Lawrence G ^a   Mani, Neelakandha S ^a   Davis, Robert L ^a   Wang, Xiao Ning ^a   Marschke, Keith B ^a   Jones, Todd K ^a,b  

^a LIGAND PHARMACEUTICALS INC   (United States)

^b Ontogen Corporation   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

4 ETHYL 1,2,3,4 TETRAHYDRO 6 (TRIFLUOROMETHYL) 8 PYRIDINO[5,6 G] QUINOLINE; ANDROGEN RECEPTOR; ANDROGEN RECEPTOR ANTAGONIST; LUTEINIZING HORMONE; QUINOLINE DERIVATIVE; TESTOSTERONE PROPIONATE; UNCLASSIFIED DRUG;

ANDROGEN METABOLISM; ANIMAL EXPERIMENT; CONTROLLED STUDY; DRUG POTENCY; DRUG RECEPTOR BINDING; DRUG STRUCTURE; DRUG SYNTHESIS; HORMONE SUBSTITUTION; HUMAN; HYPOTHALAMUS HYPOPHYSIS SYSTEM; LETTER; LUTEINIZING HORMONE RELEASE; MALE; NONHUMAN; ORAL DRUG ADMINISTRATION; RAT; STRUCTURE ACTIVITY RELATION;

ADMINISTRATION, ORAL; ANIMALS; COS CELLS; HUMANS; MALE; MOLECULAR STRUCTURE; PYRIDINES; QUINOLONES; RATS; RECEPTORS, ANDROGEN; TRANSFECTION;

EID: 0032906159     PISSN: 00222623     EISSN: None     Source Type: Journal    
DOI: 10.1021/jm9806648     Document Type: Letter

References (45)

1. (a) Wilson, J. D. Chapter 58: Androgens. In Goodman and Gilman's The Pharmacological Basis of Therapeutics, 9 ed.; Hardman, J. G., Goodman, A. G., Limbird, L. E., Eds.; McGrawHill: New York, 1996; pp 1441-1457.
2. (b) Luke, M. C.; Coffey, D. S. The Male Sex Accessory Tissues. In The Physiology of Reproduction; Knobil, E., Neill, J. D., Eds.; Raven Press: New York, 1994; pp 1435-1487.
3. (c) Mooradian, A. D.; Morley, J. E.; Korenman, S. G. Biological Actions of Androgens. Endocrine Rev. 1987, 8, 1-28.
4. 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.
5. (a) Bhasin, S.; Bremner, W. J. Emerging Issues in Androgen Replacement Therapy. J. Clin. Endocrinol. Metab. 1997, 82, 3-8.
6. (b) Peterson, C. M. The Rational Use of Androgens in Hormone Replacement Therapy. Clin. Obstet. Gynecol. 1995, 38, 915-920.
7. Bagatell, C. J.; Bremner, W. J. Androgen and Progestagen Effects on Plasma Lipids. Prog. Cardio. Dis. 1995, 38, 255-271.
8. Toomey, D.; Redmond, H. P.; Bouchier-Hayes, D. Mechanisms Mediating Cancer Cachexia. Cancer 1995, 76, 2418-2426.
9. Cummings, D. E.; Bremner, W. J. Prospects for New Hormonal Male Contraceptives. Clin. Andrology 1994, 23, 893-922.
10. (a) Bhasin, S.; Storer, T. W.; Berman, N. W.; Callgari, C.; Clevenger, B.; Phillips, J.; Bunnel, T. J.; Tricker, R.; Shirazi, A.; Casaburi, R. The Effects of Supraphysiologic Doses of Testosterone on Muscle Size and Strength in Normal Men. N. Engl. J. Med. 1996, 335, 1-7.
11. (b) Bagatell, C. J.; Bremner, W. J. Androgens in Men - Uses and Abuses. N. Eng. J. Med. 1996, 334, 707-714.
12. (a) Rasmusson, G. H.; Toney, J. H. Chapter 23. Therapeutic Control of Androgen Action. In Annual Reports in Medicinal Chemistry; Bristol, J., Ed.; Academic Press: San Diego, 1994; pp 225-234.
13. (b) Rosen, J.; Day, A.; Jones, T. K.; Jones, E. T. 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.
14. (c) Evans, R. M. The Steroid and Thyroid Hormone Receptor Superfamily. Science 1988, 240, 889-895.
15. (d) Stein, R. B. In New Drugs From Natural Sources; Coombes, I., James, D., Eds.; IBC Technical Services: Oxford, 1992; p 13.
16. (a) Findlay, J. D.; Place, V. A.; Snyder, P. J. Transdermal Delivery of Testosterone. J. Clin. Endocrinol. Metab. 1987, 64, 266-268.
17. (b) Bals-Pratsch, M.; Langer, K.; Place, V. A.; Nieschlag, E. Substitution Therapy of Hypogonadal Men with Transdermal Testosterone Over One Year. Acta Endocrinol. (Copenh.) 1988, 118, 7-13.
18. Behre, H. M.; Nieschlag, E. Testosterone Buciclate (20 Aet-1) in Hypogonadal Men: Pharmacokinetics and Pharmacodynamics of the New Long-Acting Androgen Ester. J. Clin. Endocrinol. Metab. 1992, 75, 1204-1210.
19. (a) Labrie, F. Mechanism of Action and Pure Antiandrogenic Properties of Flutamide. Cancer 1993, 72, 3816-3827.
20. (b) Furr, B. J.; Valcaccia, B.; Curry, B.; Woodburn, J. R.; Chesterson, G.; Tucker, H. ICI 176,334: A Novel Non-Steroidal, Peripherally Selective Antiandrogen. J. Endocrinol. 1987,113, R7-9.
21. (c) Furr, B. J. A. The Development of Casodex (Bicalutamide): Preclinical Studies. Eur. Urol. 1996, 29 (Suppl. 2), 83-95.
22. (d) Kolvenbag, G. J. C. M.; Blackledge, G. R. P. Worldwide Activity and Safety of Bicalutamide: A Summary Review. Urology 1996, 47 (Suppl. 1A), 70-79.
23. (a) 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.
24. (b) Edwards, J. P.; West, S. J.; Pooley, C. L. F.; Marschke, K. B.; Farmer, L. J.; Jones, T. K. New Nonsteroidal Androgen Receptor Modulators Based on 4-(Trifluoromethyl)-2(1H)-pyrrolidino[3,2-g]quinolinone. Bioorg. Med. Chem. Lett. 1998, 8, 745-750.
25. Dalton, J. T.; Mukherjee, A.; Zhu, Z.; Kirkovsky, L.; Miller, D. D. Discovery of Nonsteroidal Androgens. Biochem. Biophys. Res. Commun. 1998, 244, 1-4.
26. Katritzky, A. R.; Rachwal, S.; Rachwal, B. Recent Progress in the Synthesis of 1,2,3,4-Tetrahydroquinolines. Tetrahedron 1996, 52, 15031-15070.
27. Noyori, R.; Kato, M.; Kawanisi, M.; Nozaki, H. Photochemical Reaction of Benzopyridines with Alkanoic Acids. Novel Reductive Alkylation of Acridine, Quinoline and Isoquinoline Under Decarboxylation. Tetrahedron 1969, 25, 1125-1136.
28. (a) Kaiser, E. M.; Bartling, G. J.; Thomas, W. R.; Nichols, S. B.; Nash, D. R. Selective Metalations of Methylated Pyridines and Quinolines. Condensation Reactions. J. Org. Chem. 1973, 38, 71-75.
29. (b) Levine, R.; Dimmig, D. A.; Kadunce, W. M. Selective Acylation of 2,4-Lutidine at Its 2-and 4-Methyl Groups. J. Org. Chem. 1974, 39, 3834-3837.
30. Biaise, E. E.; Maire, M. Alkyl-4-quinolines. Mechanism of the Reaction of Skraup and of Doebner and von Miller. Bull. Soc. Chim. 1908, 3, 667-674.
31. Nose, A.; Kudo, T. Reduction of Heterocyclic Compounds. II. Reduction of Heterocyclic Compounds with Sodium Borohydride-Transition Metal Salt Systems. Chem. Pharm. Bull. 1984, 32 (6), 2421-2425.
32. (a) Knorr, L. Liebigs Ann. 1886,236, 69.
33. (b) Hodgkinson, A. J.; Staskun, B. Conversion of 2,2-Dichloroacetoacetanilides into 4-Hydroxymethyl-2(1H)-quinolones. J. Org. Chem. 1969, 34, 1709-1713.
34. (c) Jones, G. Quinolines. Part I. In The Chemistry of Heterocyclic Compounds; Weissberger, A., Taylor, E. C., Eds.; Wiley-Interscience: London, 1977; Vol. 32, pp 137-299.
35. (d) Hauser, C. R.; Reynolds, G. A. Reactions of β-Keto Esters with Aromatic Amines. Synthesis of 2-and 4-Hydroxyquinoline Derivatives. J. Am. Chem. Soc. 1948, 70, 2402-2404.
36. (a) Hollenberg, S. M.; Evans, R. M. Multiple and Cooperative Trans-Activation Domains of the Human Glucocorticoid Receptor. Cell 1988, 55, 899-906.
37. (b) Simental, J. A.; Sar, M.; Lane, M. V.; French, F. S.; Wilson, E. M. Transcriptional Activation and Nuclear Targeting Signals of the Human Androgen Receptor. J. Biol. Chem. 1991, 266, 510-518.
38. Data not shown.
39. Negro-Vilar, A.; Ojeda, S. R.; McCann, S. M. Evidence for Changes in Sensitivity to Testosterone Negative Feedback on Gonadotropin Release During Sexual Development in the Male Rat. Endocrinology 1973, 93, 729-735.
40. (a) Zhi, L.; Tegley, C. M.; Kallel, E. A.; Marschke, K. B.; Mais, D. E.; Gottardis, M. M.; Jones, T. K. 5-Aryl-1,2-dihydrochromeno-[3,4-f]quinolines: A Novel Class of Nonsteroidal Human Progesterone Receptor Agonists. J. Med. Chem. 1998, 41, 291-302.
41. (b) Edwards, J. P.; West, S. J.; Marschke, K. B.; Mais, D. E.; Gottardis, M. M.; Jones, T. K. 5-Aryl-1,2-dihydro-5H-chromeno[3,4-f]quinolines as Potent, Orally Active, Nonsteroidal Progesterone Receptor Agonists: The Effect of D-Ring Substituents. J. Med. Chem. 1998, 41, 303-310.
42. (c) Edwards, J. P.; Zhi, L.; Pooley, C L. F.; Tegley, C. M.; West, S. J.; Wang, M.-W.; Gottardis, M. M.; Pathirana, C.; Schrader, W. T.; Jones, T. K. Preparation, Resolution, and Biological Evaluation of 5-Aryl-1,2-dihydro-5K-chromeno[3,4-f]quinolines: Potent, Orally Active, Nonsteroidal Progesterone Receptor Agonists. J. Med. Chem. 1998, 41, 2779-2785.
43. (d) Tegley, C. M.; Zhi, L.; Marschke, K. B.; Gottardis, M. M.; Yang, Q.; Jones, T. K. 5-Benzylidene-1,2-dihydrochromeno-[3,4-f]quinolines, A Novel Class of Nonsteroidal Human Progesterone Receptor Agonists. J. Med. Chem. 1998, 41, 4354-4359.
44. (e) Pooley, C. L. F.; Edwards, J. P.; Goldman, M. E.; Wang, M.-W.; Marschke, K. B.; Crombie, D.; Jones, T. K. Discovery and Preliminary SAR Studies of a Novel, Nonsteroidal Progesterone Receptor Antagonist Pharmacophore. J. Med. Chem. 1998, 41, 3461-3466.
45. (f) Hamann, L. G.; Winn, D. T.; Pooley, C. L. F.; Tegley, C. M.; West, S. J.; Farmer, L. J.; Zhi, L.; Edwards, J. P.; Marschke, K. B.; Mais, D. E.; Goldman, M. E.; Jones, T. K. Nonsteroidal Progesterone Receptor Antagonists Based on a Conformationally-Restricted Subseries of 6-Aryl-1,2-dihydro-2,2,4-trimethylquinolones. Bioorg. Med. Chem. Lett. 1998, 8, 2731-2736.