Paolo Lombardi Pages 23 - 50 ( 28 )
Approximately one-third of the over 100,000 annual new breast carcinoma cases in the USA are classified as hormone-dependent. In patients with hormone-responsive neoplasms, the withdrawal of oestrogens or the alteration of oestrogens action result in tumour regression. In the last three decades clinical investigation has focused on the inhibition of oestrogen biosynthesis, since aromatase (oestrogen synthetase) is the rate-limiting enzyme in the conversion of androgens to oestrogens. More recently, aromatase became the target enzyme of specifically designed, mechanism-activated inhibitors. Such compounds should have high affinity for the enzyme, longer duration of pharmacological action, since their inactivation results by a covalent binding of the .inhibitor to the enzyme, and consequently they should show reduced toxicity with respect to both hormonal and non- . hormonal agents currently clinically available. 4-Hydroxyandrost-4-ene-3,17-dione (3), the first potent ' mechanism-based inhibitor identified, entered the market in 1993. A variety of promising compounds are currently following in advanced clinical trials. This review will update efforts toward the discovery and the synthesis of mechanism-based steroidal inhibitors of aromatase, with emphasis on those with proven efficacy in the animal, and with particular relevance to those which appeared solely in the patent literature.