5-aryl-1,2-dihydrochromeno[3,4-f]quinolines: A novel class of nonsteroidal human progesterone receptor agonists

Journal of Medicinal Chemistry

Volumn 41, Issue 3, 1998, Pages 291-302

  Zhi, Lin ^a   Tegley, Christopher M ^a   Kallel, E Adam ^a   Marschke, Keith B ^a   Mais, Dale E ^a   Gottardis, Marco M ^a   Jones, Todd K ^a  

^a LIGAND PHARMACEUTICALS INC   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

5 ARYL 1,2 DIHYDRO 2,2,4 TRIMETHYL 5H CHROMENO[3,4 F]QUINOLINE; FULVESTRANT; HORMONE RECEPTOR STIMULATING AGENT; MEDROXYPROGESTERONE ACETATE; MIFEPRISTONE; ONAPRISTONE; PROGESTERONE; PROGESTERONE RECEPTOR; PROGESTERONE RECEPTOR AGONIST; QUINOLINE DERIVATIVE; UNCLASSIFIED DRUG;

ANIMAL EXPERIMENT; ANIMAL TISSUE; ARTICLE; CONTROLLED STUDY; DRUG SELECTIVITY; ENDOMETRIUM; FEMALE; HORMONE RECEPTOR INTERACTION; HORMONE SUBSTITUTION; MAMMARY GLAND; NONHUMAN; ORAL DRUG ADMINISTRATION; OVARIECTOMY; RAT; RECEPTOR AFFINITY; STRUCTURE ACTIVITY RELATION; SUBCUTANEOUS DRUG ADMINISTRATION; UTERUS WEIGHT;

ANIMALS; BINDING, COMPETITIVE; FEMALE; HUMANS; MAGNETIC RESONANCE SPECTROSCOPY; MAMMARY GLANDS, ANIMAL; QUINOLINES; RATS; RATS, SPRAGUE-DAWLEY; RECEPTORS, ANDROGEN; RECEPTORS, ESTROGEN; RECEPTORS, GLUCOCORTICOID; RECEPTORS, MINERALOCORTICOID; RECEPTORS, PROGESTERONE; STRUCTURE-ACTIVITY RELATIONSHIP; UTERUS;

EID: 0032576697     PISSN: 00222623     EISSN: None     Source Type: Journal    
DOI: 10.1021/jm9705768     Document Type: Article

References (55)

1. Many general reviews on steroid research, including the progestins, have been published; see: (a) Witzmann, R. P. Steroids-Keys to Life; Van Norstrand Reinhold: New York, 1981. (b) Fullerton, D. S. Steroids and Therapeutically Related Compounds. In Wilson and Gisvold's Textbook of Organic Medicinal and Pharmaceutical Chemistry, 9th ed.; Delgado, J. N.; Remers, W. A., Eds.; J. B. Lippincott Co.: Philadelphia, 1991; Chapter 18. Deghenghi, R.; Givner, M. L. Female Sex Hormones. In Burger's Medicinal Chemistry; Wolff, M. E., Ed.; John Wiley & Sons: New York, 1979-1980; Chapter 29, Vol. 2. Murad, F.; Kuret, J. Estrogens and Progestins. In The Pharmaceutical Basis of Therapeutics, 8th ed.; Gilman, A. G., Rall, T. W., Nies, A. S., Taylor, P., Eds.; Macmillan: New York, 1990; Chapter 58.
2. Many general reviews on steroid research, including the progestins, have been published; see: (a) Witzmann, R. P. Steroids-Keys to Life; Van Norstrand Reinhold: New York, 1981. (b) Fullerton, D. S. Steroids and Therapeutically Related Compounds. In Wilson and Gisvold's Textbook of Organic Medicinal and Pharmaceutical Chemistry, 9th ed.; Delgado, J. N.; Remers, W. A., Eds.; J. B. Lippincott Co.: Philadelphia, 1991; Chapter 18. Deghenghi, R.; Givner, M. L. Female Sex Hormones. In Burger's Medicinal Chemistry; Wolff, M. E., Ed.; John Wiley & Sons: New York, 1979-1980; Chapter 29, Vol. 2. Murad, F.; Kuret, J. Estrogens and Progestins. In The Pharmaceutical Basis of Therapeutics, 8th ed.; Gilman, A. G., Rall, T. W., Nies, A. S., Taylor, P., Eds.; Macmillan: New York, 1990; Chapter 58.
3. Many general reviews on steroid research, including the progestins, have been published; see: (a) Witzmann, R. P. Steroids-Keys to Life; Van Norstrand Reinhold: New York, 1981. (b) Fullerton, D. S. Steroids and Therapeutically Related Compounds. In Wilson and Gisvold's Textbook of Organic Medicinal and Pharmaceutical Chemistry, 9th ed.; Delgado, J. N.; Remers, W. A., Eds.; J. B. Lippincott Co.: Philadelphia, 1991; Chapter 18. Deghenghi, R.; Givner, M. L. Female Sex Hormones. In Burger's Medicinal Chemistry; Wolff, M. E., Ed.; John Wiley & Sons: New York, 1979-1980; Chapter 29, Vol. 2. Murad, F.; Kuret, J. Estrogens and Progestins. In The Pharmaceutical Basis of Therapeutics, 8th ed.; Gilman, A. G., Rall, T. W., Nies, A. S., Taylor, P., Eds.; Macmillan: New York, 1990; Chapter 58.
4. Many general reviews on steroid research, including the progestins, have been published; see: (a) Witzmann, R. P. Steroids-Keys to Life; Van Norstrand Reinhold: New York, 1981. (b) Fullerton, D. S. Steroids and Therapeutically Related Compounds. In Wilson and Gisvold's Textbook of Organic Medicinal and Pharmaceutical Chemistry, 9th ed.; Delgado, J. N.; Remers, W. A., Eds.; J. B. Lippincott Co.: Philadelphia, 1991; Chapter 18. Deghenghi, R.; Givner, M. L. Female Sex Hormones. In Burger's Medicinal Chemistry; Wolff, M. E., Ed.; John Wiley & Sons: New York, 1979-1980; Chapter 29, Vol. 2. Murad, F.; Kuret, J. Estrogens and Progestins. In The Pharmaceutical Basis of Therapeutics, 8th ed.; Gilman, A. G., Rall, T. W., Nies, A. S., Taylor, P., Eds.; Macmillan: New York, 1990; Chapter 58.
5. Pincus, G. The Control of Fertility; Academic Press: New York, 1965; references cited therein.
6. Djerassi, C.; Miramontes, L.; Rosenkranz, G.; Sondheimer, F. Synthesis of 19-Nor-17a-ethyny]testosterone and 19-Nor-17α methyltestosterone. J. Am. Chem. Soc. 1954, 76, 4092-4094.
7. Colton, F. B. U.S. Patent 2,691,028, 1954 (applied May, 1953).
8. Breckwoldt, M.; Keck, C.; Karck, U. Benefits and Risks of Hormone Replacement Therapy (HRT). J. Steroid Biochem. Mol. Biol. 1995, 53, 205-208.
9. Mishell, D. R., Jr. Breast Cancer Risk with Oral Contraceptives and Estrogen Replacement Therapy. Aust. N. Z. J. Obstet. Gynaecol. 1994, 34, 316-320.
10. Raynaud, J. P.; Azadian-Boulanger, G.; Ojasoo, T. Expansion Scientifique Francaise. In Pharmacologie Clinique. Bases de la Therapeutique; Giroud, J. P., Mathe, G., Meyniel, G., Eds.; 1988; p 2093.
11. (a) Collins, D. C. Sex Hormone Receptor Binding, Progestin Selectivity, and the New Oral Contraceptives. Am. J. Obstet. Gynecol. 1994, 170, 1508-1513.
12. (b) Combs, D. W.; Reese, K.; Phillips, A. Nonsteroidal Progesterone Receptor Ligands. 1. 3-Aryl-1-benzoyl-1,4,5,6-tetrahydropyridazines. J. Med. Chem. 1995, 38, 4878-4879. Combs, D. W.; Reese, K., Cornelius, L. A. M.; Gunnet, J. W.; Cryan, E. V.; Granger, K. S.; Jordan, J. J.; Demarest, K. T. Nonsteroidal Progesterone Receptor Ligands. 2. High-Affinity Ligands with Selectivity for Bone Cell Progesterone Receptors. J. Med. Chem. 1995, 38, 4880-4884.
13. (b) Combs, D. W.; Reese, K.; Phillips, A. Nonsteroidal Progesterone Receptor Ligands. 1. 3-Aryl-1-benzoyl-1,4,5,6-tetrahydropyridazines. J. Med. Chem. 1995, 38, 4878-4879. Combs, D. W.; Reese, K., Cornelius, L. A. M.; Gunnet, J. W.; Cryan, E. V.; Granger, K. S.; Jordan, J. J.; Demarest, K. T. Nonsteroidal Progesterone Receptor Ligands. 2. High-Affinity Ligands with Selectivity for Bone Cell Progesterone Receptors. J. Med. Chem. 1995, 38, 4880-4884.
14. (a) Colletta, A. A.; Wakefield, L. M.; Howell, F. V.; Danielpour, D.; Baum, M.; Sporn, M. B. The Growth Inhibition of Human Breast Cancer Cells by a Novel Synthetic Progestin Involves the Induction of Transforming Growth Factor Beta. J. Clin. Invest. 1991, 87, 277-283.
15. (b) Megase (BMS oncology brand name for megestrol acetate) for breast cancer.
16. See recent reviews: (a) Evans, R. M. The Steroid and Thyroid Receptor Superfamily. Science 1988, 240, 889-895. (b) O'Malley, B. The Steroid Receptor Superfamily: More Excitement Predicted for the Future. Mol Endocrinol 1990, 4 (3), 363-369. Miesfeld, R. L. The Structure and Function of Steroid Receptor Proteins. Critical Reviews in Biochemistry and Molecular Biology. Mol. Biol. 1989, 24, 101-117. Beato, M. Gene Regulation by Steroid Hormones. Cell 1989, 56, 335-344. (e) Luisi, B. F.; Schwabe, J. W. R.; Freedman, L. P. The Steroid/ Nuclear Receptors: From Three-dimensional Structure to Complex Function. Vitamins and Hormones; Academic Press: New York, 1994; Vol. 49, pp 1-47.
17. See recent reviews: (a) Evans, R. M. The Steroid and Thyroid Receptor Superfamily. Science 1988, 240, 889-895. (b) O'Malley, B. The Steroid Receptor Superfamily: More Excitement Predicted for the Future. Mol Endocrinol 1990, 4 (3), 363-369. Miesfeld, R. L. The Structure and Function of Steroid Receptor Proteins. Critical Reviews in Biochemistry and Molecular Biology. Mol. Biol. 1989, 24, 101-117. Beato, M. Gene Regulation by Steroid Hormones. Cell 1989, 56, 335-344. (e) Luisi, B. F.; Schwabe, J. W. R.; Freedman, L. P. The Steroid/ Nuclear Receptors: From Three-dimensional Structure to Complex Function. Vitamins and Hormones; Academic Press: New York, 1994; Vol. 49, pp 1-47.
18. See recent reviews: (a) Evans, R. M. The Steroid and Thyroid Receptor Superfamily. Science 1988, 240, 889-895. (b) O'Malley, B. The Steroid Receptor Superfamily: More Excitement Predicted for the Future. Mol Endocrinol 1990, 4 (3), 363-369. Miesfeld, R. L. The Structure and Function of Steroid Receptor Proteins. Critical Reviews in Biochemistry and Molecular Biology. Mol. Biol. 1989, 24, 101-117. Beato, M. Gene Regulation by Steroid Hormones. Cell 1989, 56, 335-344. (e) Luisi, B. F.; Schwabe, J. W. R.; Freedman, L. P. The Steroid/ Nuclear Receptors: From Three-dimensional Structure to Complex Function. Vitamins and Hormones; Academic Press: New York, 1994; Vol. 49, pp 1-47.
19. See recent reviews: (a) Evans, R. M. The Steroid and Thyroid Receptor Superfamily. Science 1988, 240, 889-895. (b) O'Malley, B. The Steroid Receptor Superfamily: More Excitement Predicted for the Future. Mol Endocrinol 1990, 4 (3), 363-369. Miesfeld, R. L. The Structure and Function of Steroid Receptor Proteins. Critical Reviews in Biochemistry and Molecular Biology. Mol. Biol. 1989, 24, 101-117. Beato, M. Gene Regulation by Steroid Hormones. Cell 1989, 56, 335-344. (e) Luisi, B. F.; Schwabe, J. W. R.; Freedman, L. P. The Steroid/ Nuclear Receptors: From Three-dimensional Structure to Complex Function. Vitamins and Hormones; Academic Press: New York, 1994; Vol. 49, pp 1-47.
20. See recent reviews: (a) Evans, R. M. The Steroid and Thyroid Receptor Superfamily. Science 1988, 240, 889-895. (b) O'Malley, B. The Steroid Receptor Superfamily: More Excitement Predicted for the Future. Mol Endocrinol 1990, 4 (3), 363-369. Miesfeld, R. L. The Structure and Function of Steroid Receptor Proteins. Critical Reviews in Biochemistry and Molecular Biology. Mol. Biol. 1989, 24, 101-117. Beato, M. Gene Regulation by Steroid Hormones. Cell 1989, 56, 335-344. (e) Luisi, B. F.; Schwabe, J. W. R.; Freedman, L. P. The Steroid/ Nuclear Receptors: From Three-dimensional Structure to Complex Function. Vitamins and Hormones; Academic Press: New York, 1994; Vol. 49, pp 1-47.
21. 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 Target for Small-molecule Drug Discovery. J. Med. Chem. 1995, 38, 4855-4874.
22. Berger, T. S.; Parandoosh, Z.; Perry, B. W.; Stein, R. B. Interaction of Glucocorticoid Analogues with the Human Glucocorticoid Receptor. J. Steroid Biochem. Mol Biol. 1992, 41, 733-738.
23. Pathirana, C.; Stein, R. B.; Berger, T. S.; Fenical, W.; laniro, T.; Mais, D. E.; Torres, A.; Glodman, M. E. Nonsteroidal Human Progesterone Receptor Modulators from the Marine Alga Cymopolia barbata. Mol Pharm. 1995, 47, 630-635.
24. Jones, T. K.; Pathirana, C.; Goldman, M. E.; Hamann, L. G.; Farmer, L. J.; Ianiro, T.; Johnson, M. G.; Bender, S. L.; Mais, D. E.; Stein, R. B. Discovery of Novel Intracellular Receptor Modulating Drugs. J. Steroid Biochem. Mol. Biol. 1996, 56, 61-66.
25. Hamann, L. G.; Farmer, L. J.; Johnson, M. G.; Bender, S. L.; Mais, D. E.; Wang, M. W.; Chrombie, D.; Goldman, M. E.; Jones, T. K. Synthesis and Biological Activity of Novel Nonsteroidal Progesterone Receptor Antagonists Based on Cyclocymopol Monomethyl Ether. J. Med. Chem. 1996, 39, 1778-1789.
26. (a) Misrahi, M.; Atger, M.; d'Auriol, L.; Loosfelt, H.; Meriel, C.; Fridlansky, F.; Guiochon-Mantel, A.; Galibert, F.; Milgrom, E. Complete Amino Acid Sequence of the Human Progesterone Receptor Deduced from Cloned cDNA. Biochem. Biophys. Res. Commun. 1987, 143, 740-748.
27. (b) Sartorius, C. A.; Melville, M. Y.; Hovland, A. R.; Tung, L.; Takimoto, G. S.; Horwitz, K. B. A Third Transactivation Function (AF3) of Human Progesterone Receptors Located in the Unique N-Terminal Segment of the B-Isoform. Mol Endocrinol. 1994, 8 (10), 1347-1360.
28. (c) Clemm, D. L.; Macy, B. L.; Santiso-Mere, D.; McDonnell, D. P. Definition of the Critical Cellular Components which Distinguish between Hormone and Antihormone Activated Progesterone Receptor. J. Steroid Biochem. Mol Biol. 1995, 53, 487-495.
29. (a) Chang, C.; Kokontis, J.; Liao, S. Molecular Cloning of Human and Rat Complementary DNA Encoding Androgen Receptors. Science 1988, 240, 324-326.
30. (b) Lubahn, D. B.; Joseph, D. R.; Sullivan, P. M.; Willard, H. F.; French, F. S.; Wilson, E. M. Cloning of Human Androgen Receptor Complementary DNA and Localization to the X Chromosome. Science 1988, 240, 327-330.
31. Hollenberg, S. M.; Weinberger, C.; Ong, E. S.; Cerelli, G.; Oro, A.; Lebo, R.; Thompson, E. B.; Rosenfeld, M. G.; Evans, R. M. Primary Structure and Expression of a Functional Human Glucocorticoid Receptor cDNA. Nature 1985, 318, 635-641.
32. Green, G. L.; Gilna, P.; Waterfeield, M.; Baker, A.; Hort, Y.; Shine, J. Sequence and Expression of Human Estrogen Receptor Complementary DNA. Science 1986, 231, 1150-1154.
33. Arriza, J. L.; Weinberger, C.; Cerelli, G.; Glaser, T. M.; Handelin, G. L.; Housman, D. E.; Evans, R. M. Cloning of the Human Mineralocorticoid Receptor Complementary DNA: Structure and Functional Kinship with the Glucocorticoid Receptor. Science 1987, 237, 268-275.
34. (a) Skraup, Z. H. Eine Synthese des Chinolins. Ber. Dtsch. Chem. Ges. 1880, 13, 2086-2087.
35. (b) Eisch, J. J.; Dluzniewski, T. Mechanism of the Skraup and Doebner-von Miller Quinoline Syntheses: Cyclization of α,β-Unsaturated N-Aryliminium Salts via 1,3-Diazetidinium Ion Intermediates. J. Org. Chem. 1989, 54, 1269-1274.
36. (c) Walter, H.; Sauter, H.; Winkler, T. Eine Neue Einfache Synthese Spirocyclischer 1H-Chinolin-derivate. Helv. Chim. Acta 1992, 75, 1274-1280.
37. Migachev, G. I. Investigations in the Series of Orthosubstituted Biphenyls 1. Nitration of 2-Biphenylcarboxylic Acid and the Chemical Properties of Its Nitro Derivatives. J. Org. Chem., U.S.S.R. 1979, 15(3), 503-509.
38. The reason for the high regioselectivity is unclear. It is possible that the carbonyl group of the lactone participated in the cyclization process (Skraup reaction) and directed the regioselective process. However, in the case of an open ester instead of a lactone (4-(2′-methoxyphenyl)-3-(methoxycarbonyl)aniline), the regioselectivity was totally lost.
39. Kraus, G. A.; Frazier, K. A.; Roth, B. D.; Taschner, M. J.; Neuenschwander, K. Conversion of Lactones into Ethers. J. Org. Chem. 1981, 46, 2417-2419.
40. 2-Symmetric 2,2′-Bipyridines. Chem. Ber. 1992, 125, 1169-1190.
41. Teutsch, G. 11β-Substituted 19-Norsteroids: At the Cross Roads between Hormone Agonists and Antagonists. In Adrenal Steroid Antagonism; Agarwal, M. K., Ed.; Walter de Gruyter; Berlin, 1984; pp 43-75.
42. Neef, G.; Beier, S.; Elger, W.; Henderson, D.; Wiechert, R. New Steroids with Antiprogestational and Antiglucocorticoid Activities. Steroids 1984, 44, 349-372.
43. The dose-response curves of MPA and compounds 13, 15, and 24 will be published separately. The 3.0 mg/rat dose level results in Figures 1 and 2 are presented to simply indicate the efficacy of the novel series in this in vivo model.
44. (a) SYBYL, Tripos Associates, St. Louis, MO.
45. (b) Cramer, R. D.; Patterson, D. E.; Bunce, J. D. Comparative Molecular Field Analysis (CoMFA). 1. Effect of Shape on Binding of Steroids to Carrier Proteins. J. Am. Chem. Soc. 1988, 110, 5959-5967.
46. Kallel, E. A. Manuscript in preparation.
47. Hellberg, S.; Sjostrom, M.; Skagerberg, B.; Wold, S. Peptide Quantitative Structure-Activity Relationships, a Multivariate Approach. J. Med. Chem. 1987, 30, 1126-1135.
48. 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.
49. Still, W. C.; Kahn, M.; Mitra, A. J. Rapid Chromatographic Technique for Preparation Separation with Moderate Resolution. J. Org. Chem. 1978, 43, 2923-2924.
50. A minimum amount of 70% nitric acid is used in the first nitration, which minimizes the dilution of the fuming nitric acid during the second nitration in the one-pot procedure.
51. 50) of an Enzymatic Reaction. Biochem. Pharmacol. 1973, 22, 3099-3108.
52. Stewart, J. J. P. MOPAC: A Semiempirical Molecular Orbital Program. J. Comput.-Aided Mol. Des. 1990, 1-45.
53. Lerner, L. J.; Hilf, R.; Turkheimer, A. R.; Michel, I.; Engel, S. L. Effects of Hormone Antagonists on Morphological and Biochemical Changes Induced by Hormonal Steroids in the Immature Rat Uterus. Endocrinology 1966, 78, 111-124.
54. Sakamoto, S.; Abe, A.; Hideki, K.; Yamada, N.; Seki, K.; Ryohei, O. Effects of Estrogen and Progesterone on Thymidine Kinase Activity in the Immature Rat Uterus. Am. J. Obstet. Gynecol. 1983, 145, 711-715.
55. Michna, H.; Nishino, Y.; Schneider, M. R.; Louton, T.; El Etreby, M. F. A Bioassay for the Evaluation of Antiproliferative Potencies of Progesterone Antagonists. J. Steroid Biochem. Mol. Biol. 1991, 38, 359-365.