Steroidal aromatase inhibitors type I inhibitors

Aromatase inhibitors are normally classified as steroidal (type I) or nonsteroidal (type II). Numerous steroidal agents have been developed that exhibit either competitive inhibition, irreversible inhibition, or mechanism-based inhibition of aromatase.24 Mechanism-based inhibitors are bound to the catalytic site of the enzyme, which transforms them into electrophilic intermediates that become irreversibly attached to the enzyme, blocking its activity, and they are known as ''aromatase inactivators.'' This type of inhibitors have distinct advantages in drug design, since they are highly enzyme specific, produce prolonged inhibition, and exhibit minimal toxicities, and for this reason the steroidal aromatase inhibitors in clinical use behave as mechanism-based irreversible inhibitors.25

Although the precise chemical details are sometimes not known, many types of compounds containing latent electrophilic groups intended to be activated by aromatase are known. The most relevant are summarized below.

4.2.1. C-19-modified substrate analogs

The first group steroidal aromatase inhibitors are C-19-modified substrate analogs. One example is the propargyl derivative plomestane, for which two main types of mechanisms have been proposed. The first one postulates its oxidation by aromatase to give the C-19 carbonyl derivative, leading to the Michael acceptor 3.22, a substrate for nucleophilic attack by nucleophiles at the enzyme active site. The second mechanism is based on the one proposed for the inactivation of cytochrome P450 enzymes by terminal acetylenic compounds and involves epox-idation of the acetylene chain by aromatase to give the unstable oxirene 3.24 that reacts with aromatase to give 3.27 following rearrangement to ketene 3.26 (Fig. 3.17). The development of plomestane as an antitumor drug was halted because of ''technical problems.'' 6

4.2.2. 4-Hydroxyandrostenedione derivatives

The main representative of this group is formestane. This compound was first described as a competitive inhibitor, but subsequent evidence proved that its binding to aromatase was irreversible. The presence of the C-19 methyl group is essential, since the 19-nor derivative is not an aromatase inactivator, and this suggests that the 19-oxygenated metabolites are the inactivating species. The 4-hydroxy group is also essential, and the ethers and esters of formestane at O-4 are inactive. One possible mechanism that is consistent with these

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