Aromatase inhibitors. Synthesis and biological activity of androstenedione derivatives

Abstract

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 (50-81%) 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.

Variation in Aromatase Activity in the Medial Preoptic Area and Plasma Progesterone Is Associated with the Onset of Paternal Behavior

“…In the time course study aliquots of homogenate pool were incubated for 30, 60, 90, 120, and 240 min. We also determined the effects of the competitive aromatase antagonist 4-OH-AE [46]at 10 µ M. Finally, we conducted a dose-response study using the aromatase antagonist fadrozole at 5 serial dilutions.…”

Aromatase inhibitors and enzyme stability.

“…However, it also inhibits the cholesterol side-chain cleavage reaction by P450scc, resulting in a deficiency of glucocorticoids and mineralocorticoids in addition to sex steroids. 4-Hydroxyandrostenedione (4-OHA) was subsequently utilized as a potent and specific inhibitor (Marsh et al 1985), functioning as a mechanism-based inhibitor or a suicide substrate and causing time-dependent inactivation in the presence of cofactors (Brodie et al 1981b). More recently, more potent and selective non-steroidal inhibitors of imidazole, triazole, and tetrazole derivatives have been developed and clinically examined (Brodie 1994).…”

Neonatal hormone manipulations and the maintenance of perineal muscles and their motor neurones in Albino Swiss rats

“…14, < 005). (Brodie et al, 1977;Marsh et al, 1985), while 4-MA prevents the 5ot-reduction of testosterone to DHT (Liang & Heiss, 1981;Liang et al, 1983). Each inhibitor was administered in arachis oil and control males (N = 10) received oil vehicle alone.…”