The enzyme and inhibitors of 4-ene-3-oxosteroid 5 alpha-oxidoreductase.
Since evidence of 5 alpha-reductase activity in rabbit liver homogenate was discovered in 1954, the presence of this enzyme has been demonstrated in many other organs and tissues of mammalian species. 5 alpha-Reductase selectively transforms a 4-ene-3-oxosteroid (e.g., testosterone) irreversibly to the corresponding 5 alpha-3-oxosteroid (e.g., 5 alpha-dihydrotestosterone) in the presence of NADPH as an essential coenzyme at an optimal pH. However, excessive production of 5 alpha-dihydrotestosterone is the major cause of many androgen-related disorders, such as prostate cancer, benign prostatic hyperplasia, acne, female hirsutism, and male pattern baldness; therefore, inhibition of androgenic action by 5 alpha-reductase inhibitors is a logical treatment. During the past two decades, research has focused on understanding the biological functions and effects of 5 alpha-reductase and its 5 alpha-reduced metabolites: purification of the enzyme, substrates, and metabolites; characterization of their physical, chemical, and biochemical properties; analysis of the amino acid sequence of the enzyme; synthesis of various classes of molecules as potential inhibitors; and examination of the biological activity of the inhibitors in vitro and/or in vivo. This review summarizes the biochemical studies on this enzyme, suggests the mechanisms of action of the enzyme or inhibitors, and discusses the chemistry necessary for the preparation, structure-activity relationships, and in vitro and/or in vivo data obtained from the evaluation of nonsteroidal and steroidal compounds that have been tested as inhibitors of 5 alpha-reductase. In particular, IC50 and Ki values for relevant compounds will be compared according to molecular class. This review could function as a comprehensive working reference of what research has been accomplished so far and what problems remain to be solved in the future for those engaged in this interesting field.
Li
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Medicinal Chemistry Division, C.H.U.L. Research Center, Québec, Canada.
Chen
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Singh
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Labrie
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Labire F [corrected to Labrie
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D013741:3-Oxo-5-alpha-Steroid 4-Dehydrogenase / Q000378:metabolism*; D058891:5-alpha Reductase Inhibitors; D000726:Androgen Antagonists / Q000737:chemistry / Q000494:pharmacology; D000818:Animals; D001378:Azasteroids / Q000737:chemistry / Q000494:pharmacology; D013196:Dihydrotestosterone / Q000031:analogs & derivatives / Q000737:chemistry / Q000494:pharmacology; D018120:Finasteride / Q000737:chemistry / Q000494:pharmacology; D009249:NADP / Q000494:pharmacology; D015363:Quinolones / Q000494:pharmacology; D013256:Steroids / Q000494:pharmacology; D013329:Structure-Activity Relationship
D058891:5-alpha Reductase Inhibitors; D000726:Androgen Antagonists; D001378:Azasteroids; D015363:Quinolones; D013256:Steroids; D013196:Dihydrotestosterone; D009249:NADP; D018120:Finasteride; C031563:17-N,N-diethylcarbamoyl-4-methyl-4-azaandrostane-3-one; D013741:3-Oxo-5-alpha-Steroid 4-Dehydrogenase