New Potent Inhibitors of 3β-Hydroxy-Δ⁵-steroid Oxidoreductase with Short Duration of Action

Abstract

The in vitro and in vivo effects of some new inhibitors of 3β-hydroxy-Δ5-steroid oxidoreductase have been compared to the effects of the previously known inhibitors, 2α-cyano-4,4,17α trimethyl–5-androsten-17β-ol-3-one (I) and 17β-hydroxy- 4,4,17α-trimethyl–5-androsten-(2,3d)-isoxazole (II). All of the new inhibitors are as potent as I and II in inhibiting the conversion of dehydroepiandrosterone to androstenedione and pregnenolone to progesterone by testicular microsomes. All of the inhibitors, including I and II, also inhibit in vitro C17–20 lyase as manifested by diminished formation of androstenedione and testosterone from 17α-hydroxyprogesterone. in vivo, I, II, III (α, 16α-dicyano-4,4′-dimethyl–5-pregnene-3,20-dione) and VII (2α-cyano-4,4′-dimethyl-2′,3′-tetrahydrofuran- 2′-spiro-17–5-androsten-3-one) alters adrenal and ovarian steroidogenesis with a concomitant excretion of 3β-hydroxy-Δ5-steroidal precursors for at least as long as 7 days after a single dose. The remaining three steroids produce similar derangements in urinary and biliary steroidal excretion patterns but for a much shorter period. IV (2α-cyano-17-methylspiro (5-androstene-4,4′-cyclopropan)-17β-ol-3-one) acts for about 12 hr, while V (16α-cyano-6,16β-dimethyl–5-pregnen-3β-ol-20-one) and VI (16αcyano- 4,4′-dimethyl-5-pregnen-2,3d-isoxazole) act during about 36 hr. These new synthetic cyanosteroids present a choice of potent inhibitors of 3β-hydroxy-Δ5-steroid oxidoreductase of short and intermediate duration of action. (Endocrinology95: 238, 1974)