Overview of recent development of aromatase inhibitors.

Since the first publication in 1973 concerning aromatase inhibitors, several effective compounds have been reported by a number of investigators. Our studies with 4-hydroxyandrostene-3,17-dione, 4-acetoxyandrostene-3,17-dione, and 1,-4,6-androstatrienedione indicate that these compounds cause rapid competitive inhibition of the enzyme. Aminoglutethimide binds competitively to cytochrome P-450 and inhibits a number of steroid hydroxylations but is more active as an aromatase inhibitor. 16 alpha-Bromoandrogens and 7 alpha-(4'-amino)phenylthioandrostenedione are also reported to be aromatase inhibitors. As yet, only some of these compounds have been evaluated in vivo, but all appear to be similarly effective in inhibiting aromatization in breast tumors in vitro. Recent interest has focused on enzyme inactivators or "suicide" inhibitors. Such compounds act as substrates for the enzyme but are converted by the normal catalytic mechanism of the enzyme to reactive intermediates. These then bind covalently to the active site of the enzyme causing loss of activity. Active site-directed inhibitors are usually quite specific and have long-lasting effects in vivo. A number of new compounds, as well as some of the above compounds, appear to be inactivators of aromatase and are potentially interesting as agents for hormone-dependent breast cancer therapy.