Glenn F. Reynolds

5α-Reductase inhibitory and anti-androgenic activities of some 4-azasteroids in the rat

Abstract Inhibition of 5α-reductase and anti-androgenicity were studied in rats treated with various 4-azasteroids. The known inhibitor, N,N-diethyl-4-methyl-3-oxo-4-aza-5 α-androstane-17 β-carboxamide (4-MA) served as a reference compound, and analogs of this basic molecule were assayed. Enhancement of enzyme inhibitory potency was usually seen with Δ1 analogs, whereas reduction in activity was noted with substitutuents such as Δ5, a spirotetrahydrofuran ring at C-17 or 4-deaza groups. Many of the 4-azasteroids had a much greater oral anti-androgenic effect against testosterone propionate (TP) than dihydrotestosterone propionate (DHTP). This difference in activity versus the two androgens is believed to reflect the necessity for TP to undergo reduction to DHT before becoming capable of stimulating prostatic growth. Inhibition of 5α-reductase by active compounds prevented the conversion, thereby producing an anti-androgenic effect. In this regard, certain Δ1 analogs of 4-MA, particularly those bearing a 17β-(N-tert butylcarbamoyl) group, proved very effective against TP but were relatively inactive versus DHTP.

Biological Activities of a New Steroidal Inhibitor of δ4-5α-Reductase

Abstract 17β-N,N-Diethylcarbamoyl-4-methyl-4-aza-5α-androstan-3-one (4-MA), a known 5α-reductase inhibitor, was tested in a variety of bioassays designed to document its endocrinological spectrum. It proved to be a relatively nontoxic compound which showed little or no antifertility activity in either male or female rats, no significant estrogenic, progestational, androgenic, or gonadotropin-inhibiting potency, and it did not affect serum prolactin levels. 4-MA did, however, cause feminization of male fetuses carried by treated pregnant female rats. It also caused a cessation in growth of the ventral prostate and seminal vesicles of young adult male rats. Both the feminization of male fetuses and the inhibition of male sex accessory growth are believed to be a result of the inhibition of 5α-reductase by 4-MA.

Topical anti-androgenicity of a new 4-azasteroid in the hamster

The topical anti-androgenic activity of L-651,580 (methyl 3-oxo-4-methyl-4-aza-5 alpha-androst-1-ene-17 beta-carboxylate) was established in a series of for experiments using castrated male hamsters. During each 21-day experiment, the animals received a daily subcutaneous injection of 40 micrograms testosterone propionate or 20 micrograms dihydrotestosterone propionate. Test compound in 25 microliters of gel was applied daily to the left flank organ. Compounds assayed included L-651,580, WIN 17,665 (17 alpha-propyltestosterone), and SH-434 (17 beta-hydroxy-1 alpha-methyl-17 alpha-propyl-5 alpha-androstan-3-one). Endpoints were flank organ area, sebaceous gland area, and prostate weight. Very similar results were obtained with L-651,580 and WIN 17,665. Daily doses of 0.25 mg or more of either compound usually produced a significant reduction in the areas of treated flank organs and sebaceous glands underlying treated flank organs. Neither compound caused significant changes in the area of the contralateral flank organs and sebaceous glands, which indicated they possess little or no systemic activity at topically effective treatment levels. In direct comparisons, SH-434 was less anti-androgenic than L-651,580 or WIN 17,665, although in one experiment, 0.5 mg/d of SH-434 significantly reduced the area of treated flank organs and sebaceous glands. Neither WIN 17,665 nor SH-434 caused a change in prostate weight; however, in one of four tests, a significant decrease was induced by the 0.5 mg/d level of L-651,580. The results of these experiments show that the topical anti-androgenicity of L-651,580 compares very favorably with that of WIN 17,665 and SH-434. They also indicate that the topical administration of effective dosage levels of L-651,580 causes few, if any, systemic effects.

Selenium dioxide oxidation of vitamin D3 acetate to a dimer of 1-oxotransvitamin D3 acetate

The treatment of vitamin D3 acetate with selenium dioxide and t-butyl hydroperoxide leads to a mixture from which a Diels-Alder dimer of 1-oxotransvitamin D3 acetate was isolated.