Indole derivatives as a new class of steroid 5α-reductase inhibitors

Journal of Medicinal Chemistry

Volumn 39, Issue 26, 1996, Pages 5047-5052

  Takami, Hitoshi ^a   Koshimura, Hirokazu ^a   Kishibayashi, Nobuyuki ^a   Ishii, Akio ^a   Nonaka, Hiromi ^a   Aoyama, Shiro ^a   Kase, Hiroshi ^a   Kumazawa, Toshiaki ^a  

^a KYOWA HAKKO KOGYO CO LTD   (Japan)

Author keywords

[No Author keywords available]

Indexed keywords

4 [2 [4 (4 ISOBUTYL ALPHA METHYLBENZYLOXY) 2,3 DIMETHYLBENZAMIDO]PHENOXY]BUTYRIC ACID; BUTYRIC ACID DERIVATIVE; FINASTERIDE; INDOLE DERIVATIVE; KF 18678; KF 20405; STEROID 5ALPHA REDUCTASE INHIBITOR; UNCLASSIFIED DRUG;

ANIMAL EXPERIMENT; ANIMAL TISSUE; ARTICLE; DRUG POTENCY; DRUG SCREENING; DRUG STRUCTURE; DRUG SYNTHESIS; ENZYME INHIBITION; MALE; NONHUMAN; ORAL DRUG ADMINISTRATION; RAT;

ANIMALS; ENZYME INHIBITORS; HUMANS; ISOENZYMES; MAGNETIC RESONANCE SPECTROSCOPY; MALE; PROSTATE; RATS; RATS, WISTAR; TESTOSTERONE 5-ALPHA-REDUCTASE;

EID: 0030447189     PISSN: 00222623     EISSN: None     Source Type: Journal    
DOI: 10.1021/jm9601819     Document Type: Article

References (37)

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7. For recent studies of steroidal inhibitors of 5α-reductase, see: (a) Rasmusson, G. H.; Reynolds, G. F.; Utne, T.; Jobson, R. B.; Primka, R. L.; Berman, C.; Brooks, J. R. Azasteroids as Inhibitors of Rat Prostatic 5α-Reductase. J. Med. Chem. 1984, 27, 1690-1701. (b) Rasmusson, G. H.; Reynolds, G. F.; Steinberg, N. G.; Walton, E.; Patel, G. F.; Liang, T.; Cascieri, M. A.; Cheung, A. H.; Brooks, J. R.; Berman, C. Azasteroids: Structure-Activity Relationships for Inhibition of 5α-Reductase and of Androgen Receptor Binding. J. Med. Chem. 1986, 29, 2298-2315. (c) Holt, D. A.; Levy, M. A.; Ladd, D. L.; Oh, H.-J.; Erb, J. M.; Heaslip, J. I.; Brandt, M.; Metcalf, B. W. Steroidal A-Ring Aryl Carboxylic Acids: A New Class of Steroid 5α-Reductase Inhibitors. J. Med. Chem. 1990, 33, 937-942. (d) Holt, D. A.; Levy, M. A.; Oh, H.-J.; Erb, J. M.; Heaslip, J. I.; Brandt, M.; Lan-Hargest, H. Y.; Metcalf, B. W. Inhibition of Steroid 5α-Reductase by Unsaturated 3-Carboxysteroids. J. Med. Chem. 1990, 33, 943-950. (e) Levy, M. A.; Metcalf, B. W.; Brandt, M.; Erb, J. M.; Oh, H.-J.; Heaslip, J. I.; Yen, H.-K.; Rozamus, L. W.; Holt, D. A. 3-Phosphinic Acid and 3-Phosphinic Acid Steroids as Inhibitors of 5α-Reductase: Species Comparison and Mechanistic Studies. Bioorg. Chem. 1991, 19, 245-260. (f) Haase-Held, M.; Hatzis, M.; Mann, J. The Synthesis 4-Cyano- progesterone: A Potent Inhibitor of the Enzyme 5α-Reductase. J. Chem. Soc., Perkin Trans. 1 1992, 2999-3000. (g) Frye, S. V.; Haffner, C. D.; Maloney, P. R.; Mook, R. A., Jr.; Dorsey, G. F., Jr.; Hiner, R. N.; Cribbs, C. M.; Wheeler, T. N.; Ray, J. A.; Andrews, R. C.; Batchelor, K. W.; Bramson, H. N.; Stuart, J. D.; Schweiker, S. L.; Arnold, J. V.; Croom, S.; Bickett, D. M.; Moss, M. L.; Tian, G.; Unwalla, R. J.; Lee, F. W.; Tippin, T. K.; James, M. K.; Grizzle, M. K.; Long, J. E.; Schuster, S. V. 6-Azasteroids: Structure-Activity Relationships for Inhibition of Type 1 and Type 2 Human 5α-Reductase and Human Adrenal 3β-Hydroxy-D5-steroid Dehydrogenase/3-Keto-D5-steroid Isomerase. J. Med. Chem. 1994, 37, 2352-2360. (h) Haffner, C. An Efficient Synthesis of 3-Pyridyl-N- oxide Steroids: Inhibitors of 5α-Reductase. Tetrahedron Lett. 1994, 35, 1349-1352.
8. For recent studies of steroidal inhibitors of 5α-reductase, see: (a) Rasmusson, G. H.; Reynolds, G. F.; Utne, T.; Jobson, R. B.; Primka, R. L.; Berman, C.; Brooks, J. R. Azasteroids as Inhibitors of Rat Prostatic 5α-Reductase. J. Med. Chem. 1984, 27, 1690-1701. (b) Rasmusson, G. H.; Reynolds, G. F.; Steinberg, N. G.; Walton, E.; Patel, G. F.; Liang, T.; Cascieri, M. A.; Cheung, A. H.; Brooks, J. R.; Berman, C. Azasteroids: Structure-Activity Relationships for Inhibition of 5α-Reductase and of Androgen Receptor Binding. J. Med. Chem. 1986, 29, 2298-2315. (c) Holt, D. A.; Levy, M. A.; Ladd, D. L.; Oh, H.-J.; Erb, J. M.; Heaslip, J. I.; Brandt, M.; Metcalf, B. W. Steroidal A-Ring Aryl Carboxylic Acids: A New Class of Steroid 5α-Reductase Inhibitors. J. Med. Chem. 1990, 33, 937-942. (d) Holt, D. A.; Levy, M. A.; Oh, H.-J.; Erb, J. M.; Heaslip, J. I.; Brandt, M.; Lan-Hargest, H. Y.; Metcalf, B. W. Inhibition of Steroid 5α-Reductase by Unsaturated 3-Carboxysteroids. J. Med. Chem. 1990, 33, 943-950. (e) Levy, M. A.; Metcalf, B. W.; Brandt, M.; Erb, J. M.; Oh, H.-J.; Heaslip, J. I.; Yen, H.-K.; Rozamus, L. W.; Holt, D. A. 3-Phosphinic Acid and 3-Phosphinic Acid Steroids as Inhibitors of 5α-Reductase: Species Comparison and Mechanistic Studies. Bioorg. Chem. 1991, 19, 245-260. (f) Haase-Held, M.; Hatzis, M.; Mann, J. The Synthesis 4-Cyano- progesterone: A Potent Inhibitor of the Enzyme 5α-Reductase. J. Chem. Soc., Perkin Trans. 1 1992, 2999-3000. (g) Frye, S. V.; Haffner, C. D.; Maloney, P. R.; Mook, R. A., Jr.; Dorsey, G. F., Jr.; Hiner, R. N.; Cribbs, C. M.; Wheeler, T. N.; Ray, J. A.; Andrews, R. C.; Batchelor, K. W.; Bramson, H. N.; Stuart, J. D.; Schweiker, S. L.; Arnold, J. V.; Croom, S.; Bickett, D. M.; Moss, M. L.; Tian, G.; Unwalla, R. J.; Lee, F. W.; Tippin, T. K.; James, M. K.; Grizzle, M. K.; Long, J. E.; Schuster, S. V. 6-Azasteroids: Structure-Activity Relationships for Inhibition of Type 1 and Type 2 Human 5α-Reductase and Human Adrenal 3β-Hydroxy-D5-steroid Dehydrogenase/3-Keto-D5-steroid Isomerase. J. Med. Chem. 1994, 37, 2352-2360. (h) Haffner, C. An Efficient Synthesis of 3-Pyridyl-N- oxide Steroids: Inhibitors of 5α-Reductase. Tetrahedron Lett. 1994, 35, 1349-1352.
9. For recent studies of steroidal inhibitors of 5α-reductase, see: (a) Rasmusson, G. H.; Reynolds, G. F.; Utne, T.; Jobson, R. B.; Primka, R. L.; Berman, C.; Brooks, J. R. Azasteroids as Inhibitors of Rat Prostatic 5α-Reductase. J. Med. Chem. 1984, 27, 1690-1701. (b) Rasmusson, G. H.; Reynolds, G. F.; Steinberg, N. G.; Walton, E.; Patel, G. F.; Liang, T.; Cascieri, M. A.; Cheung, A. H.; Brooks, J. R.; Berman, C. Azasteroids: Structure-Activity Relationships for Inhibition of 5α-Reductase and of Androgen Receptor Binding. J. Med. Chem. 1986, 29, 2298-2315. (c) Holt, D. A.; Levy, M. A.; Ladd, D. L.; Oh, H.-J.; Erb, J. M.; Heaslip, J. I.; Brandt, M.; Metcalf, B. W. Steroidal A-Ring Aryl Carboxylic Acids: A New Class of Steroid 5α-Reductase Inhibitors. J. Med. Chem. 1990, 33, 937-942. (d) Holt, D. A.; Levy, M. A.; Oh, H.-J.; Erb, J. M.; Heaslip, J. I.; Brandt, M.; Lan-Hargest, H. Y.; Metcalf, B. W. Inhibition of Steroid 5α-Reductase by Unsaturated 3-Carboxysteroids. J. Med. Chem. 1990, 33, 943-950. (e) Levy, M. A.; Metcalf, B. W.; Brandt, M.; Erb, J. M.; Oh, H.-J.; Heaslip, J. I.; Yen, H.-K.; Rozamus, L. W.; Holt, D. A. 3-Phosphinic Acid and 3-Phosphinic Acid Steroids as Inhibitors of 5α-Reductase: Species Comparison and Mechanistic Studies. Bioorg. Chem. 1991, 19, 245-260. (f) Haase-Held, M.; Hatzis, M.; Mann, J. The Synthesis 4-Cyano- progesterone: A Potent Inhibitor of the Enzyme 5α-Reductase. J. Chem. Soc., Perkin Trans. 1 1992, 2999-3000. (g) Frye, S. V.; Haffner, C. D.; Maloney, P. R.; Mook, R. A., Jr.; Dorsey, G. F., Jr.; Hiner, R. N.; Cribbs, C. M.; Wheeler, T. N.; Ray, J. A.; Andrews, R. C.; Batchelor, K. W.; Bramson, H. N.; Stuart, J. D.; Schweiker, S. L.; Arnold, J. V.; Croom, S.; Bickett, D. M.; Moss, M. L.; Tian, G.; Unwalla, R. J.; Lee, F. W.; Tippin, T. K.; James, M. K.; Grizzle, M. K.; Long, J. E.; Schuster, S. V. 6-Azasteroids: Structure-Activity Relationships for Inhibition of Type 1 and Type 2 Human 5α-Reductase and Human Adrenal 3β-Hydroxy-D5-steroid Dehydrogenase/3-Keto-D5-steroid Isomerase. J. Med. Chem. 1994, 37, 2352-2360. (h) Haffner, C. An Efficient Synthesis of 3-Pyridyl-N- oxide Steroids: Inhibitors of 5α-Reductase. Tetrahedron Lett. 1994, 35, 1349-1352.
10. For recent studies of steroidal inhibitors of 5α-reductase, see: (a) Rasmusson, G. H.; Reynolds, G. F.; Utne, T.; Jobson, R. B.; Primka, R. L.; Berman, C.; Brooks, J. R. Azasteroids as Inhibitors of Rat Prostatic 5α-Reductase. J. Med. Chem. 1984, 27, 1690-1701. (b) Rasmusson, G. H.; Reynolds, G. F.; Steinberg, N. G.; Walton, E.; Patel, G. F.; Liang, T.; Cascieri, M. A.; Cheung, A. H.; Brooks, J. R.; Berman, C. Azasteroids: Structure-Activity Relationships for Inhibition of 5α-Reductase and of Androgen Receptor Binding. J. Med. Chem. 1986, 29, 2298-2315. (c) Holt, D. A.; Levy, M. A.; Ladd, D. L.; Oh, H.-J.; Erb, J. M.; Heaslip, J. I.; Brandt, M.; Metcalf, B. W. Steroidal A-Ring Aryl Carboxylic Acids: A New Class of Steroid 5α-Reductase Inhibitors. J. Med. Chem. 1990, 33, 937-942. (d) Holt, D. A.; Levy, M. A.; Oh, H.-J.; Erb, J. M.; Heaslip, J. I.; Brandt, M.; Lan-Hargest, H. Y.; Metcalf, B. W. Inhibition of Steroid 5α-Reductase by Unsaturated 3-Carboxysteroids. J. Med. Chem. 1990, 33, 943-950. (e) Levy, M. A.; Metcalf, B. W.; Brandt, M.; Erb, J. M.; Oh, H.-J.; Heaslip, J. I.; Yen, H.-K.; Rozamus, L. W.; Holt, D. A. 3-Phosphinic Acid and 3-Phosphinic Acid Steroids as Inhibitors of 5α-Reductase: Species Comparison and Mechanistic Studies. Bioorg. Chem. 1991, 19, 245-260. (f) Haase-Held, M.; Hatzis, M.; Mann, J. The Synthesis 4-Cyano- progesterone: A Potent Inhibitor of the Enzyme 5α-Reductase. J. Chem. Soc., Perkin Trans. 1 1992, 2999-3000. (g) Frye, S. V.; Haffner, C. D.; Maloney, P. R.; Mook, R. A., Jr.; Dorsey, G. F., Jr.; Hiner, R. N.; Cribbs, C. M.; Wheeler, T. N.; Ray, J. A.; Andrews, R. C.; Batchelor, K. W.; Bramson, H. N.; Stuart, J. D.; Schweiker, S. L.; Arnold, J. V.; Croom, S.; Bickett, D. M.; Moss, M. L.; Tian, G.; Unwalla, R. J.; Lee, F. W.; Tippin, T. K.; James, M. K.; Grizzle, M. K.; Long, J. E.; Schuster, S. V. 6-Azasteroids: Structure-Activity Relationships for Inhibition of Type 1 and Type 2 Human 5α-Reductase and Human Adrenal 3β-Hydroxy-D5-steroid Dehydrogenase/3-Keto-D5-steroid Isomerase. J. Med. Chem. 1994, 37, 2352-2360. (h) Haffner, C. An Efficient Synthesis of 3-Pyridyl-N- oxide Steroids: Inhibitors of 5α-Reductase. Tetrahedron Lett. 1994, 35, 1349-1352.
11. For recent studies of steroidal inhibitors of 5α-reductase, see: (a) Rasmusson, G. H.; Reynolds, G. F.; Utne, T.; Jobson, R. B.; Primka, R. L.; Berman, C.; Brooks, J. R. Azasteroids as Inhibitors of Rat Prostatic 5α-Reductase. J. Med. Chem. 1984, 27, 1690-1701. (b) Rasmusson, G. H.; Reynolds, G. F.; Steinberg, N. G.; Walton, E.; Patel, G. F.; Liang, T.; Cascieri, M. A.; Cheung, A. H.; Brooks, J. R.; Berman, C. Azasteroids: Structure-Activity Relationships for Inhibition of 5α-Reductase and of Androgen Receptor Binding. J. Med. Chem. 1986, 29, 2298-2315. (c) Holt, D. A.; Levy, M. A.; Ladd, D. L.; Oh, H.-J.; Erb, J. M.; Heaslip, J. I.; Brandt, M.; Metcalf, B. W. Steroidal A-Ring Aryl Carboxylic Acids: A New Class of Steroid 5α-Reductase Inhibitors. J. Med. Chem. 1990, 33, 937-942. (d) Holt, D. A.; Levy, M. A.; Oh, H.-J.; Erb, J. M.; Heaslip, J. I.; Brandt, M.; Lan-Hargest, H. Y.; Metcalf, B. W. Inhibition of Steroid 5α-Reductase by Unsaturated 3-Carboxysteroids. J. Med. Chem. 1990, 33, 943-950. (e) Levy, M. A.; Metcalf, B. W.; Brandt, M.; Erb, J. M.; Oh, H.-J.; Heaslip, J. I.; Yen, H.-K.; Rozamus, L. W.; Holt, D. A. 3-Phosphinic Acid and 3-Phosphinic Acid Steroids as Inhibitors of 5α-Reductase: Species Comparison and Mechanistic Studies. Bioorg. Chem. 1991, 19, 245-260. (f) Haase-Held, M.; Hatzis, M.; Mann, J. The Synthesis 4-Cyano- progesterone: A Potent Inhibitor of the Enzyme 5α-Reductase. J. Chem. Soc., Perkin Trans. 1 1992, 2999-3000. (g) Frye, S. V.; Haffner, C. D.; Maloney, P. R.; Mook, R. A., Jr.; Dorsey, G. F., Jr.; Hiner, R. N.; Cribbs, C. M.; Wheeler, T. N.; Ray, J. A.; Andrews, R. C.; Batchelor, K. W.; Bramson, H. N.; Stuart, J. D.; Schweiker, S. L.; Arnold, J. V.; Croom, S.; Bickett, D. M.; Moss, M. L.; Tian, G.; Unwalla, R. J.; Lee, F. W.; Tippin, T. K.; James, M. K.; Grizzle, M. K.; Long, J. E.; Schuster, S. V. 6-Azasteroids: Structure-Activity Relationships for Inhibition of Type 1 and Type 2 Human 5α-Reductase and Human Adrenal 3β-Hydroxy-D5-steroid Dehydrogenase/3-Keto-D5-steroid Isomerase. J. Med. Chem. 1994, 37, 2352-2360. (h) Haffner, C. An Efficient Synthesis of 3-Pyridyl-N- oxide Steroids: Inhibitors of 5α-Reductase. Tetrahedron Lett. 1994, 35, 1349-1352.
12. For recent studies of steroidal inhibitors of 5α-reductase, see: (a) Rasmusson, G. H.; Reynolds, G. F.; Utne, T.; Jobson, R. B.; Primka, R. L.; Berman, C.; Brooks, J. R. Azasteroids as Inhibitors of Rat Prostatic 5α-Reductase. J. Med. Chem. 1984, 27, 1690-1701. (b) Rasmusson, G. H.; Reynolds, G. F.; Steinberg, N. G.; Walton, E.; Patel, G. F.; Liang, T.; Cascieri, M. A.; Cheung, A. H.; Brooks, J. R.; Berman, C. Azasteroids: Structure-Activity Relationships for Inhibition of 5α-Reductase and of Androgen Receptor Binding. J. Med. Chem. 1986, 29, 2298-2315. (c) Holt, D. A.; Levy, M. A.; Ladd, D. L.; Oh, H.-J.; Erb, J. M.; Heaslip, J. I.; Brandt, M.; Metcalf, B. W. Steroidal A-Ring Aryl Carboxylic Acids: A New Class of Steroid 5α-Reductase Inhibitors. J. Med. Chem. 1990, 33, 937-942. (d) Holt, D. A.; Levy, M. A.; Oh, H.-J.; Erb, J. M.; Heaslip, J. I.; Brandt, M.; Lan-Hargest, H. Y.; Metcalf, B. W. Inhibition of Steroid 5α-Reductase by Unsaturated 3-Carboxysteroids. J. Med. Chem. 1990, 33, 943-950. (e) Levy, M. A.; Metcalf, B. W.; Brandt, M.; Erb, J. M.; Oh, H.-J.; Heaslip, J. I.; Yen, H.-K.; Rozamus, L. W.; Holt, D. A. 3-Phosphinic Acid and 3-Phosphinic Acid Steroids as Inhibitors of 5α-Reductase: Species Comparison and Mechanistic Studies. Bioorg. Chem. 1991, 19, 245-260. (f) Haase-Held, M.; Hatzis, M.; Mann, J. The Synthesis 4-Cyano- progesterone: A Potent Inhibitor of the Enzyme 5α-Reductase. J. Chem. Soc., Perkin Trans. 1 1992, 2999-3000. (g) Frye, S. V.; Haffner, C. D.; Maloney, P. R.; Mook, R. A., Jr.; Dorsey, G. F., Jr.; Hiner, R. N.; Cribbs, C. M.; Wheeler, T. N.; Ray, J. A.; Andrews, R. C.; Batchelor, K. W.; Bramson, H. N.; Stuart, J. D.; Schweiker, S. L.; Arnold, J. V.; Croom, S.; Bickett, D. M.; Moss, M. L.; Tian, G.; Unwalla, R. J.; Lee, F. W.; Tippin, T. K.; James, M. K.; Grizzle, M. K.; Long, J. E.; Schuster, S. V. 6-Azasteroids: Structure-Activity Relationships for Inhibition of Type 1 and Type 2 Human 5α-Reductase and Human Adrenal 3β-Hydroxy-D5-steroid Dehydrogenase/3-Keto-D5-steroid Isomerase. J. Med. Chem. 1994, 37, 2352-2360. (h) Haffner, C. An Efficient Synthesis of 3-Pyridyl-N- oxide Steroids: Inhibitors of 5α-Reductase. Tetrahedron Lett. 1994, 35, 1349-1352.
13. For recent studies of steroidal inhibitors of 5α-reductase, see: (a) Rasmusson, G. H.; Reynolds, G. F.; Utne, T.; Jobson, R. B.; Primka, R. L.; Berman, C.; Brooks, J. R. Azasteroids as Inhibitors of Rat Prostatic 5α-Reductase. J. Med. Chem. 1984, 27, 1690-1701. (b) Rasmusson, G. H.; Reynolds, G. F.; Steinberg, N. G.; Walton, E.; Patel, G. F.; Liang, T.; Cascieri, M. A.; Cheung, A. H.; Brooks, J. R.; Berman, C. Azasteroids: Structure-Activity Relationships for Inhibition of 5α-Reductase and of Androgen Receptor Binding. J. Med. Chem. 1986, 29, 2298-2315. (c) Holt, D. A.; Levy, M. A.; Ladd, D. L.; Oh, H.-J.; Erb, J. M.; Heaslip, J. I.; Brandt, M.; Metcalf, B. W. Steroidal A-Ring Aryl Carboxylic Acids: A New Class of Steroid 5α-Reductase Inhibitors. J. Med. Chem. 1990, 33, 937-942. (d) Holt, D. A.; Levy, M. A.; Oh, H.-J.; Erb, J. M.; Heaslip, J. I.; Brandt, M.; Lan-Hargest, H. Y.; Metcalf, B. W. Inhibition of Steroid 5α-Reductase by Unsaturated 3-Carboxysteroids. J. Med. Chem. 1990, 33, 943-950. (e) Levy, M. A.; Metcalf, B. W.; Brandt, M.; Erb, J. M.; Oh, H.-J.; Heaslip, J. I.; Yen, H.-K.; Rozamus, L. W.; Holt, D. A. 3-Phosphinic Acid and 3-Phosphinic Acid Steroids as Inhibitors of 5α-Reductase: Species Comparison and Mechanistic Studies. Bioorg. Chem. 1991, 19, 245-260. (f) Haase-Held, M.; Hatzis, M.; Mann, J. The Synthesis 4-Cyano- progesterone: A Potent Inhibitor of the Enzyme 5α-Reductase. J. Chem. Soc., Perkin Trans. 1 1992, 2999-3000. (g) Frye, S. V.; Haffner, C. D.; Maloney, P. R.; Mook, R. A., Jr.; Dorsey, G. F., Jr.; Hiner, R. N.; Cribbs, C. M.; Wheeler, T. N.; Ray, J. A.; Andrews, R. C.; Batchelor, K. W.; Bramson, H. N.; Stuart, J. D.; Schweiker, S. L.; Arnold, J. V.; Croom, S.; Bickett, D. M.; Moss, M. L.; Tian, G.; Unwalla, R. J.; Lee, F. W.; Tippin, T. K.; James, M. K.; Grizzle, M. K.; Long, J. E.; Schuster, S. V. 6-Azasteroids: Structure-Activity Relationships for Inhibition of Type 1 and Type 2 Human 5α-Reductase and Human Adrenal 3β-Hydroxy-D5-steroid Dehydrogenase/3-Keto-D5-steroid Isomerase. J. Med. Chem. 1994, 37, 2352-2360. (h) Haffner, C. An Efficient Synthesis of 3-Pyridyl-N- oxide Steroids: Inhibitors of 5α-Reductase. Tetrahedron Lett. 1994, 35, 1349-1352.
14. For recent studies of steroidal inhibitors of 5α-reductase, see: (a) Rasmusson, G. H.; Reynolds, G. F.; Utne, T.; Jobson, R. B.; Primka, R. L.; Berman, C.; Brooks, J. R. Azasteroids as Inhibitors of Rat Prostatic 5α-Reductase. J. Med. Chem. 1984, 27, 1690-1701. (b) Rasmusson, G. H.; Reynolds, G. F.; Steinberg, N. G.; Walton, E.; Patel, G. F.; Liang, T.; Cascieri, M. A.; Cheung, A. H.; Brooks, J. R.; Berman, C. Azasteroids: Structure-Activity Relationships for Inhibition of 5α-Reductase and of Androgen Receptor Binding. J. Med. Chem. 1986, 29, 2298-2315. (c) Holt, D. A.; Levy, M. A.; Ladd, D. L.; Oh, H.-J.; Erb, J. M.; Heaslip, J. I.; Brandt, M.; Metcalf, B. W. Steroidal A-Ring Aryl Carboxylic Acids: A New Class of Steroid 5α-Reductase Inhibitors. J. Med. Chem. 1990, 33, 937-942. (d) Holt, D. A.; Levy, M. A.; Oh, H.-J.; Erb, J. M.; Heaslip, J. I.; Brandt, M.; Lan-Hargest, H. Y.; Metcalf, B. W. Inhibition of Steroid 5α-Reductase by Unsaturated 3-Carboxysteroids. J. Med. Chem. 1990, 33, 943-950. (e) Levy, M. A.; Metcalf, B. W.; Brandt, M.; Erb, J. M.; Oh, H.-J.; Heaslip, J. I.; Yen, H.-K.; Rozamus, L. W.; Holt, D. A. 3-Phosphinic Acid and 3-Phosphinic Acid Steroids as Inhibitors of 5α-Reductase: Species Comparison and Mechanistic Studies. Bioorg. Chem. 1991, 19, 245-260. (f) Haase-Held, M.; Hatzis, M.; Mann, J. The Synthesis 4-Cyano- progesterone: A Potent Inhibitor of the Enzyme 5α-Reductase. J. Chem. Soc., Perkin Trans. 1 1992, 2999-3000. (g) Frye, S. V.; Haffner, C. D.; Maloney, P. R.; Mook, R. A., Jr.; Dorsey, G. F., Jr.; Hiner, R. N.; Cribbs, C. M.; Wheeler, T. N.; Ray, J. A.; Andrews, R. C.; Batchelor, K. W.; Bramson, H. N.; Stuart, J. D.; Schweiker, S. L.; Arnold, J. V.; Croom, S.; Bickett, D. M.; Moss, M. L.; Tian, G.; Unwalla, R. J.; Lee, F. W.; Tippin, T. K.; James, M. K.; Grizzle, M. K.; Long, J. E.; Schuster, S. V. 6-Azasteroids: Structure-Activity Relationships for Inhibition of Type 1 and Type 2 Human 5α-Reductase and Human Adrenal 3β-Hydroxy-D5-steroid Dehydrogenase/3-Keto-D5-steroid Isomerase. J. Med. Chem. 1994, 37, 2352-2360. (h) Haffner, C. An Efficient Synthesis of 3-Pyridyl-N- oxide Steroids: Inhibitors of 5α-Reductase. Tetrahedron Lett. 1994, 35, 1349-1352.
15. (i) Stoner, E. The Clinical Development of a 5α-Reductase Inhibitor, Finasteride. J. Steroid Biochem. Mol. Biol. 1990, 37, 375-378.
16. For recent studies of nonsteroidal inhibitors of 5α-reductase, see: (a) Nakai, H.; Terashima, H; Arai, Y. Benzoylaminophenoxybutanoic Acid Derivatives. Ono Pharmaceutical Co., Ltd. EP 0 291 245, 1988; Chem. Abstr. 1989, 110, 212384t, 708. (b) Jones, C. D.; Audia, J. E.; Lawhorn, D. E.; McQuaid, L. A.; Nerbauer, B. L.; Pike, A. J.; Pennington, P. A.; Stamm, N. B.; Toomey, R. E.; Hirsch, K. S. Nonsteroidal Inhibitors of Human Type 1 Steroid 5α-reductase. J. Med. Chem. 1993, 36, 421-423. (c) Audia, J. E.; Lawhorn D. E.; Deeter, J. B. Synthesis of the Individual Enantiomera of the Benzoquinolinone Human Type 1 Steroid 5α-reductase Inhibitors LY191704 and LY266111. Tetrahedron Lett. 1993, 34, 7001-7004. (d) Abell, A. D. A Non-steroidal Diene Acid Inhibitor of Human Type 2 Steroid 5α-reductase. Bioorg. Med. Chem. Lett. 1994, 4, 2327-2330. (e) Holt, D. A.; Yarnashita, D. S.; Konialian-Beck, A. L.; Luengo, J. I.; Abell, A. D.; Bergsma, D. J.; Brandt, M.; Levy, M. A. Benzophenone- and Indolecarboxylic Acid: Potent Type-2 Specific Inhibitors of Human Steroid 5α-reductase. J. Med. Chem. 1995, 38, 13-15.
17. For recent studies of nonsteroidal inhibitors of 5α-reductase, see: (a) Nakai, H.; Terashima, H; Arai, Y. Benzoylaminophenoxybutanoic Acid Derivatives. Ono Pharmaceutical Co., Ltd. EP 0 291 245, 1988; Chem. Abstr. 1989, 110, 212384t, 708. (b) Jones, C. D.; Audia, J. E.; Lawhorn, D. E.; McQuaid, L. A.; Nerbauer, B. L.; Pike, A. J.; Pennington, P. A.; Stamm, N. B.; Toomey, R. E.; Hirsch, K. S. Nonsteroidal Inhibitors of Human Type 1 Steroid 5α-reductase. J. Med. Chem. 1993, 36, 421-423. (c) Audia, J. E.; Lawhorn D. E.; Deeter, J. B. Synthesis of the Individual Enantiomera of the Benzoquinolinone Human Type 1 Steroid 5α-reductase Inhibitors LY191704 and LY266111. Tetrahedron Lett. 1993, 34, 7001-7004. (d) Abell, A. D. A Non-steroidal Diene Acid Inhibitor of Human Type 2 Steroid 5α-reductase. Bioorg. Med. Chem. Lett. 1994, 4, 2327-2330. (e) Holt, D. A.; Yarnashita, D. S.; Konialian-Beck, A. L.; Luengo, J. I.; Abell, A. D.; Bergsma, D. J.; Brandt, M.; Levy, M. A. Benzophenone- and Indolecarboxylic Acid: Potent Type-2 Specific Inhibitors of Human Steroid 5α-reductase. J. Med. Chem. 1995, 38, 13-15.
18. For recent studies of nonsteroidal inhibitors of 5α-reductase, see: (a) Nakai, H.; Terashima, H; Arai, Y. Benzoylaminophenoxybutanoic Acid Derivatives. Ono Pharmaceutical Co., Ltd. EP 0 291 245, 1988; Chem. Abstr. 1989, 110, 212384t, 708. (b) Jones, C. D.; Audia, J. E.; Lawhorn, D. E.; McQuaid, L. A.; Nerbauer, B. L.; Pike, A. J.; Pennington, P. A.; Stamm, N. B.; Toomey, R. E.; Hirsch, K. S. Nonsteroidal Inhibitors of Human Type 1 Steroid 5α-reductase. J. Med. Chem. 1993, 36, 421-423. (c) Audia, J. E.; Lawhorn D. E.; Deeter, J. B. Synthesis of the Individual Enantiomera of the Benzoquinolinone Human Type 1 Steroid 5α-reductase Inhibitors LY191704 and LY266111. Tetrahedron Lett. 1993, 34, 7001-7004. (d) Abell, A. D. A Non-steroidal Diene Acid Inhibitor of Human Type 2 Steroid 5α-reductase. Bioorg. Med. Chem. Lett. 1994, 4, 2327-2330. (e) Holt, D. A.; Yarnashita, D. S.; Konialian-Beck, A. L.; Luengo, J. I.; Abell, A. D.; Bergsma, D. J.; Brandt, M.; Levy, M. A. Benzophenone- and Indolecarboxylic Acid: Potent Type-2 Specific Inhibitors of Human Steroid 5α-reductase. J. Med. Chem. 1995, 38, 13-15.
19. For recent studies of nonsteroidal inhibitors of 5α-reductase, see: (a) Nakai, H.; Terashima, H; Arai, Y. Benzoylaminophenoxybutanoic Acid Derivatives. Ono Pharmaceutical Co., Ltd. EP 0 291 245, 1988; Chem. Abstr. 1989, 110, 212384t, 708. (b) Jones, C. D.; Audia, J. E.; Lawhorn, D. E.; McQuaid, L. A.; Nerbauer, B. L.; Pike, A. J.; Pennington, P. A.; Stamm, N. B.; Toomey, R. E.; Hirsch, K. S. Nonsteroidal Inhibitors of Human Type 1 Steroid 5α-reductase. J. Med. Chem. 1993, 36, 421-423. (c) Audia, J. E.; Lawhorn D. E.; Deeter, J. B. Synthesis of the Individual Enantiomera of the Benzoquinolinone Human Type 1 Steroid 5α-reductase Inhibitors LY191704 and LY266111. Tetrahedron Lett. 1993, 34, 7001-7004. (d) Abell, A. D. A Non-steroidal Diene Acid Inhibitor of Human Type 2 Steroid 5α-reductase. Bioorg. Med. Chem. Lett. 1994, 4, 2327-2330. (e) Holt, D. A.; Yarnashita, D. S.; Konialian-Beck, A. L.; Luengo, J. I.; Abell, A. D.; Bergsma, D. J.; Brandt, M.; Levy, M. A. Benzophenone- and Indolecarboxylic Acid: Potent Type-2 Specific Inhibitors of Human Steroid 5α-reductase. J. Med. Chem. 1995, 38, 13-15.
20. For recent studies of nonsteroidal inhibitors of 5α-reductase, see: (a) Nakai, H.; Terashima, H; Arai, Y. Benzoylaminophenoxybutanoic Acid Derivatives. Ono Pharmaceutical Co., Ltd. EP 0 291 245, 1988; Chem. Abstr. 1989, 110, 212384t, 708. (b) Jones, C. D.; Audia, J. E.; Lawhorn, D. E.; McQuaid, L. A.; Nerbauer, B. L.; Pike, A. J.; Pennington, P. A.; Stamm, N. B.; Toomey, R. E.; Hirsch, K. S. Nonsteroidal Inhibitors of Human Type 1 Steroid 5α-reductase. J. Med. Chem. 1993, 36, 421-423. (c) Audia, J. E.; Lawhorn D. E.; Deeter, J. B. Synthesis of the Individual Enantiomera of the Benzoquinolinone Human Type 1 Steroid 5α-reductase Inhibitors LY191704 and LY266111. Tetrahedron Lett. 1993, 34, 7001-7004. (d) Abell, A. D. A Non-steroidal Diene Acid Inhibitor of Human Type 2 Steroid 5α-reductase. Bioorg. Med. Chem. Lett. 1994, 4, 2327-2330. (e) Holt, D. A.; Yarnashita, D. S.; Konialian-Beck, A. L.; Luengo, J. I.; Abell, A. D.; Bergsma, D. J.; Brandt, M.; Levy, M. A. Benzophenone- and Indolecarboxylic Acid: Potent Type-2 Specific Inhibitors of Human Steroid 5α-reductase. J. Med. Chem. 1995, 38, 13-15.
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