COMPARATIVE MOLECULAR-FIELD ANALYSIS OF NONSTEROIDAL AROMATASE INHIBITORS - AN EXTENDED MODEL FOR 2 DIFFERENT STRUCTURAL CLASSES

Aromatase is a cytochrome P450 isozyme, whose inhibition is known to b e therapeutically relevant in the treatment of the breast cancer. A co mparative molecular field analysis (CoMFA) has been carried out on a s eries of non-steroidal aromatase inhibitors belonging to two different structural classes. One subset of compounds consists of fadrozole ana logues and was studied in a previous work, from which a 'local' 3-D qu antitative structure-activity relationship (QSAR) model for the inhibi tion of aromatase was obtained. In the present paper, that model is ex tended to include a second subset of compounds bearing a tetralone nuc leus and acting at the same enzyme site with the same mechanism as the azoles. The critical alignment step has been solved by using two diff erent steroidal inhibitors of aromatase as rigid templates, on which t he non-steroidal compounds have been superimposed. The final 3-D QSAR models are discussed in terms of predictivity and some implications re garding the steric and electronic requirements of steroidal and non-st eroidal inhibitors are pointed out. (C) 1998 Elsevier Science Ltd. All rights reserved.