Skip to main content
NCBI home page
Proceedings of the National Academy of Sciences of the United States of America logoLink to Proceedings of the National Academy of Sciences of the United States of America
. 1993 Jun 1;90(11):5277–5281. doi: 10.1073/pnas.90.11.5277

LY191704: a selective, nonsteroidal inhibitor of human steroid 5 alpha-reductase type 1.

K S Hirsch 1, C D Jones 1, J E Audia 1, S Andersson 1, L McQuaid 1, N B Stamm 1, B L Neubauer 1, P Pennington 1, R E Toomey 1, D W Russell 1
PMCID: PMC46699  PMID: 8389478

Abstract

Androgens, in particular dihydrotestosterone (DHT), play a key role in differentiation, growth, and maintenance of the mammalian prostate. Production of DHT from testosterone is catalyzed by two distinct membrane-bound steroid 5 alpha-reductase [5 alpha-reductase; 3-oxo-5 alpha-steroid delta 4-dehydrogenase; 3-oxo-5 alpha-steroid:(acceptor) delta 4-oxidoreductase, EC 1.3.99.5] isozymes designated types 1 and 2. Benign prostatic hyperplasia (BPH), a disease that occurs almost universally in males, is characterized by obstructive and irritative urinary voiding symptoms and has been associated with an overproduction of DHT. Recently, steroidal inhibitors of 5 alpha-reductase type 2 have been used successfully for treatment of BPH. Described here is a nonsteroidal inhibitor of 5 alpha-reductase type 1, LY191704 (8-chloro-4-methyl-1,2,3,4,4a,5,6,10b-octaahydro-benzo[f]quinol in-3(2H)-one). This compound was identified based on its capacity to inhibit 5 alpha-reductase activity in a human genital skin fibroblast cell line (Hs68). Surprisingly, LY191704 is inactive when tested in freshly isolated prostate cells obtained from subjects with BPH, whereas previously described 4-azasteroids are active. LY191704 is, however, a potent inhibitor of the 5 alpha-reductase activity of BPH cells that have been maintained in culture. Analysis of human and rat 5 alpha-reductases expressed from transfected cDNAs in simian COS cells indicates that LY191704 is a specific noncompetitive inhibitor of the human 5 alpha-reductase type 1. Taken together, the results suggest that prostate cells have the capacity to express both 5 alpha-reductase isozymes and that LY191704 may be useful in treatment of human endocrine disorders associated with overproduction of DHT by 5 alpha-reductase type 1.

Full text

PDF
5277

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Andersson S., Berman D. M., Jenkins E. P., Russell D. W. Deletion of steroid 5 alpha-reductase 2 gene in male pseudohermaphroditism. Nature. 1991 Nov 14;354(6349):159–161. doi: 10.1038/354159a0. [DOI] [PMC free article] [PubMed] [Google Scholar]
  2. Andersson S., Bishop R. W., Russell D. W. Expression cloning and regulation of steroid 5 alpha-reductase, an enzyme essential for male sexual differentiation. J Biol Chem. 1989 Sep 25;264(27):16249–16255. [PMC free article] [PubMed] [Google Scholar]
  3. Andersson S., Russell D. W. Structural and biochemical properties of cloned and expressed human and rat steroid 5 alpha-reductases. Proc Natl Acad Sci U S A. 1990 May;87(10):3640–3644. doi: 10.1073/pnas.87.10.3640. [DOI] [PMC free article] [PubMed] [Google Scholar]
  4. Bradford M. M. A rapid and sensitive method for the quantitation of microgram quantities of protein utilizing the principle of protein-dye binding. Anal Biochem. 1976 May 7;72:248–254. doi: 10.1016/0003-2697(76)90527-3. [DOI] [PubMed] [Google Scholar]
  5. Diani A. R., Mulholland M. J., Shull K. L., Kubicek M. F., Johnson G. A., Schostarez H. J., Brunden M. N., Buhl A. E. Hair growth effects of oral administration of finasteride, a steroid 5 alpha-reductase inhibitor, alone and in combination with topical minoxidil in the balding stumptail macaque. J Clin Endocrinol Metab. 1992 Feb;74(2):345–350. doi: 10.1210/jcem.74.2.1309834. [DOI] [PubMed] [Google Scholar]
  6. Djøseland O., Bruchovsky N., Rennie P. S., Otal N., Høglo S. 5 alpha-reductase activity in stroma and epithelium of rat prostate and epididymis. A contribution to elucidation of the mechanism for development of hyperplastic growth of prostatic tissue. Acta Endocrinol (Copenh) 1983 Jun;103(2):273–281. doi: 10.1530/acta.0.1030273. [DOI] [PubMed] [Google Scholar]
  7. Durocher Y., Chapdelaine A., Chevalier S. Tyrosine protein kinase activity of human hyperplastic prostate and carcinoma cell lines PC3 and DU145. Cancer Res. 1989 Sep 1;49(17):4818–4823. [PubMed] [Google Scholar]
  8. Esser V., Limbird L. E., Brown M. S., Goldstein J. L., Russell D. W. Mutational analysis of the ligand binding domain of the low density lipoprotein receptor. J Biol Chem. 1988 Sep 15;263(26):13282–13290. [PubMed] [Google Scholar]
  9. Hierowski M. T., McDonald M. W., Dunn L., Sullivan J. W. The partial dependency of human prostatic growth factor on steroid hormones in stimulating thymidine incorporation into DNA. J Urol. 1987 Oct;138(4):909–912. doi: 10.1016/s0022-5347(17)43414-8. [DOI] [PubMed] [Google Scholar]
  10. Itami S., Kurata S., Sonoda T., Takayasu S. Characterization of 5 alpha-reductase in cultured human dermal papilla cells from beard and occipital scalp hair. J Invest Dermatol. 1991 Jan;96(1):57–60. doi: 10.1111/1523-1747.ep12514729. [DOI] [PubMed] [Google Scholar]
  11. Jenkins E. P., Andersson S., Imperato-McGinley J., Wilson J. D., Russell D. W. Genetic and pharmacological evidence for more than one human steroid 5 alpha-reductase. J Clin Invest. 1992 Jan;89(1):293–300. doi: 10.1172/JCI115574. [DOI] [PMC free article] [PubMed] [Google Scholar]
  12. Kyprianou N., Isaacs J. T. Identification of a cellular receptor for transforming growth factor-beta in rat ventral prostate and its negative regulation by androgens. Endocrinology. 1988 Oct;123(4):2124–2131. doi: 10.1210/endo-123-4-2124. [DOI] [PubMed] [Google Scholar]
  13. Liang T., Cascieri M. A., Cheung A. H., Reynolds G. F., Rasmusson G. H. Species differences in prostatic steroid 5 alpha-reductases of rat, dog, and human. Endocrinology. 1985 Aug;117(2):571–579. doi: 10.1210/endo-117-2-571. [DOI] [PubMed] [Google Scholar]
  14. Liang T., Rasmusson G. H., Brooks J. R. 12. Androgens: Pharmacodynamics and antagonists. Biochemical and biological studies with 4-aza-steroidal 5 alpha-reductase inhibitors. J Steroid Biochem. 1983 Jul;19(1A):385–390. doi: 10.1016/s0022-4731(83)80051-x. [DOI] [PubMed] [Google Scholar]
  15. Matzkin H., Braf Z. Endocrine treatment of benign prostatic hypertrophy: current concepts. Urology. 1991 Jan;37(1):1–16. doi: 10.1016/0090-4295(91)80069-j. [DOI] [PubMed] [Google Scholar]
  16. Metcalf B. W., Levy M. A., Holt D. A. Inhibitors of steroid 5 alpha-reductase in benign prostatic hyperplasia, male pattern baldness and acne. Trends Pharmacol Sci. 1989 Dec;10(12):491–495. doi: 10.1016/0165-6147(89)90048-5. [DOI] [PubMed] [Google Scholar]
  17. Moore R. J., Wilson J. D. Steroid 5alpha-reductase in cultured human fibroblasts. Biochemical and genetic evidence for two distinct enzyme activities. J Biol Chem. 1976 Oct 10;251(19):5895–5900. [PubMed] [Google Scholar]
  18. Rittmaster R. S., Uno H., Povar M. L., Mellin T. N., Loriaux D. L. The effects of N,N-diethyl-4-methyl-3-oxo-4-aza-5 alpha-androstane-17 beta-carboxamide, a 5 alpha-reductase inhibitor and antiandrogen, on the development of baldness in the stumptail macaque. J Clin Endocrinol Metab. 1987 Jul;65(1):188–193. doi: 10.1210/jcem-65-1-188. [DOI] [PubMed] [Google Scholar]
  19. Schweikert H. U., Wilson J. D. Regulation of human hair growth by steroid hormones. I. Testerone metabolism in isolated hairs. J Clin Endocrinol Metab. 1974 May;38(5):811–819. doi: 10.1210/jcem-38-5-811. [DOI] [PubMed] [Google Scholar]
  20. Smith R. A., Wake R., Soloway M. S. Benign prostatic hyperplasia. Universal problem among aging men. Postgrad Med. 1988 May 1;83(6):79–85. doi: 10.1080/00325481.1988.11700255. [DOI] [PubMed] [Google Scholar]
  21. Stimson J. B., Fihn S. D. Benign prostatic hyperplasia and its treatment. J Gen Intern Med. 1990 Mar-Apr;5(2):153–165. doi: 10.1007/BF02600518. [DOI] [PubMed] [Google Scholar]
  22. Stoner E. The clinical development of a 5 alpha-reductase inhibitor, finasteride. J Steroid Biochem Mol Biol. 1990 Nov 20;37(3):375–378. doi: 10.1016/0960-0760(90)90487-6. [DOI] [PubMed] [Google Scholar]
  23. Thigpen A. E., Russell D. W. Four-amino acid segment in steroid 5 alpha-reductase 1 confers sensitivity to finasteride, a competitive inhibitor. J Biol Chem. 1992 Apr 25;267(12):8577–8583. [PubMed] [Google Scholar]
  24. Wright R. S. A reagent for the non-destructive location of steroids and some other lipophilic materials on silica gel thin-layer chromatograms. J Chromatogr. 1971 Jul 8;59(1):220–221. doi: 10.1016/s0021-9673(01)80033-9. [DOI] [PubMed] [Google Scholar]

Articles from Proceedings of the National Academy of Sciences of the United States of America are provided here courtesy of National Academy of Sciences

RESOURCES