5 alpha-reductase inhibitors, chemical and clinical models.
An active site model of 5 alpha-reductase type 2 isoenzyme on an "active-analog approach" and based on 4-azasteroidal inhibitors has been constructed to evaluate the effects on the inhibitory potency of substituents on the steroid A ring. This model has proven able to predict the potential inhibitory activity of 19-nor-10-azasteroid and 6-azasteroid compounds. A model for the evaluation of clinical efficacy of an inhibitor, based on in vitro data, has also been developed and applied to finasteride. This inhibitory potency evaluation of finasteride in human scalp homogenates, plus pharmacokinetic data, allows the calculation of a theoretical in situ inhibition value for human scalp. From the IC50 curve of finasteride in scalp homogenates, it is possible to calculate that for an inhibition level similar to that obtained in prostate with 5 mg of finasteride, the necessary plasma concentration of the drug is 1 microM, a level obtained after the acute administration of 50 mg of finasteride.
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Department of Organic Chemistry Ugo Schiff, University of Florence, Italy.
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D042944:Cholestenone 5 alpha-Reductase; D004341:Drug Evaluation; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D018120:Finasteride / Q000737:chemistry / Q000494:pharmacology; D006801:Humans; D008954:Models, Biological; D008956:Models, Chemical; D010088:Oxidoreductases / Q000037:antagonists & inhibitors*
D004791:Enzyme Inhibitors; D018120:Finasteride; D010088:Oxidoreductases; D042944:Cholestenone 5 alpha-Reductase