Aromatase inhibitors: synthesis, biological activity, and binding mode of azole-type compounds.

The enantiomers of the potent nonsteroidal inhibitor of aromatase fadrozole hydrochloride 3 have been separated and their absolute configuration determined by X-ray crystallography. On the basis of a molecular modeling comparison of the active enantiomer 4 and one of the most potent steroidal inhibitors reported to date, (19R)-10-thiiranylestr-4-ene-3,17-dione, 7, a model describing the relative binding modes of the azole-type and steroidal inhibitors of aromatase at the active site of the enzyme is proposed. It is suggested that the cyanophenyl moiety present in the most active azole inhibitors partially mimics the steroid backbone of the natural substrate for aromatase, androst-4-ene-3,17-dione, 1. The synthesis and biological testing of novel analogues of 3 used to define the accessible and nonaccessible volumes to ligands in the model of the active site of aromatase are reported.