New potent inhibitors of 3β-hydroxy-Δ⁵-steroid oxidoreductase with short duration of action

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 trimethyl5-androsten-17β-ol-3-one (I) and 17β-hydroxy- 4, 4, 17α-trimethyl5-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 C₁₇₂₀ lyase as manifested by diminished formation of androstenedione and testosterone from 17α-hydroxyprogesterone. in vivo, I, II, III (α, 16α-dicyano-4, 4′-dimethyl5-pregnene-3, 20-dione) and VII (2α-cyano-4, 4′-dimethyl-2′, 3′-tetrahydrofuran- 2′-spiro-175-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-dimethyl5-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.