Aromatase inhibitors. Synthesis and biological activity of androstenedione derivatives

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Abstract
The synthesis and biological evaluation of androstenedione derivatives as inhibitors of estrogen biosynthesis are described. 4-Hydroxy analogs are among the most potent in vitro inhibitors of the series. Esterification of the 4-hydroxy steroids generally reduced activity. Further conjugation of the 3-keto 4-ene system to give 4-hydroxy-4,6-androstadiene-3,17-dione caused more rapid inactivation of aromatase in rat ovarian microsomes than 4-hydroxyandrostenedione. Some compounds exhibited differences in activity when tested for inhibition of human placental microsomes vs. rat ovarian microsomes. The 4-hydroxyandrostenedione derivatives and their nonbulky esters were generally more potent in vitro and in vivo inhibitors than other substituted steroids in the series. Several of the synthesized compounds markedly reduced (50-81%) estrogen levels in rats on proestrus and/or had antifertility action. To date, none of the compounds surpassed the in vivo inhibitory action of 4-hydroxy-4-androstene-3,17-dione or its 4-acetate derivative. [Compounds affecting aromatase (estrogen synthetase) inhibition have application as research tools for investigating estrogen-mediated processes and are of potential clinical value for controlling estrogen-mediated events, such as ovulation and the growth of estrogen-dependent tumors.].

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