3 beta-hydroxyandrost-4-en-6-one derivatives as aromatase inhibitors.

The 3-formate (II), 3-acetate (III), 3-bromoacetate (IV), 3-propionate (V), 3-methyl ether (VI), and 3-deoxy-derivative (VII) of 3 beta-hydroxyandrost-4-ene-6,17-dione (I) were synthesized and tested in human placental microsomes for their ability to inhibit aromatase. II, III, and VII of this series were potent inhibitors of aromatase with the IC50's (1.7 and 3.3 microM) of the latter two comparable to that (1.2 microM) of 4-hydroxyandrostenedione. Kinetic studies showed that the three steroids are competitive inhibitors of the enzyme with Ki's of 16.0, 5.5, and 0.61 microM for II, III, and VII. Furthermore, II showed a time-dependent, pseudo-first order rate of inactivation of aromatase with Ki of 20.5 microM and kinact of 1.54 x 10(-2) min-1, while III gave a time-dependent, biphasic loss of the enzyme activity. NADPH and oxygen were required for the time-dependent inactivation and the substrate, androstenedione, prevented it.