Structure-activity relationships and binding model of novel aromatase inhibitors

The use of aromatase inhibitors is an established therapy for oestrogen-dependent breast cancer in postmenopausal women. However, the sole commercially available aromatase inhibitor, aminoglutethimide, is not very selective. We have therefore developed fadrozole hydrochloride and CGS 20 267, which are both currently under clinical evaluation. This report will present an analysis of structure-activity relationships in the azole series of inhibitors and give an account of the further optimization of our development compounds, starting from CGS 20 267 over CGP 45 688 and leading to CGP 47 645, the most potent aromatase inhibitors in vivo reported to date. In addition, on the basis of comparisons of these azole-type inhibitors with the most potent steroidal inhibitors published in the literature, we propose a CAMM-generated model describing the relative binding modes of these two classes of compounds at the active site of the enzyme.