(5 alpha, 20S)-4-Diazo-21-hydroxy-20-methylpregnan-3-one, a mechanism-based inhibitor of testosterone 5 alpha-reductase, produced pronounced and long lasting inhibition of the enzyme in the prostate and preputial glands when administered orally to rats. Administration of the inhibitor to castrate rats bearing testosterone implants produced inhibition of growth of the prostate, seminal vesicles,and preputial glands, but had no effect on growth of the levator ani muscle. (5 alpha-20S)-4-Diazo-21-hydroxy-20-methylpregnan-3-one did not antagonize growth of the accessory sex organs induced by 5 alpha-dihydrotestosterone (5 alpha-DHT). The inhibitor thus produced a pure 5 alpha-reductase deficiency in the rat without detectable receptor-level antagonism, and with consequences similar to those occurring at puberty in the 5 alpha-reductase-deficient human male: reduction of 5 alpha-DHT-mediated processes and maintenance of those mediated by testosterone. The results emphasize the importance of the enzymatic profiles of individual organs in determining selective response to testosterone or 5 alpha-DHT. Evidence is presented which indicates that the testes are the source of circulating 5 alpha-DHT in the immature rat.

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MDL 18,962, 19-acetylenic androstenedione, is an enzyme-activated inhibitor of estrogen biosynthesis which is in Phase I clinical evaluations as a potential therapeutic agent for estrogen-dependent cancers. 19-Acetylenic analogs corresponding to the major metabolites of androstenedione were synthesized as potential metabolites of MDL 18,962. These compounds were 19-acetylenic testosterone, the product of 17 beta-hydroxy steroid oxidoreductase, 6 beta-hydroxy- and 6-oxo-19-acetylenic androstenedione, products of P450 steroid 6 beta-hydroxylase and alcohol dehydrogenase, respectively. All of these analogs showed time-dependent inactivation of human placental aromatase activity. The time-dependent Ki and t1/2 at infinite inhibitor concentration (tau 50) were 4.3 nM, 12.0 min for MDL 18,962; 28 nM, 7.8 min for 17-hydroxy analog; 13 nM, 37 min for 6 beta-hydroxy analog; and 167 nM, 6.1 min for the 6-oxo analog. The 19-acetylenic testosterone, a confirmed metabolite from primate studies, was 25% as efficient as MDL 18,962 for aromatase inactivation, while 6 beta-hydroxy- and 6-oxo analogs were 11% and 5%, respectively as efficient as their parent compound. These data indicate that first-pass metabolism of MDL 18,962 does not cause an obligatory loss of time-dependent inhibition of human aromatase activity.

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