Aromatase Inhibitors. Synthesis and Biological Activity of Androstenedione Derivatives

Article abstract of DOI:10.1021/jm00383a017

The synthesis and biological evaluation of androstenedione derivatives as inhibitors of estrogen biosynthesis are described.The results show that 4-hydroxy analogues 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 reduce (50-81percent) 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.