Molecular shape and QSAR analyses of a family of substituted dichlorodiphenyl aromatase inhibitors.

Conformational analyses of three families of substituted dichlorodiphenyl aromatase inhibitors indicated that both potent and weak inhibitors adopt a common global minimum energy conformation. Further, this global minimum energy conformation is the only meaningful intramolecular conformer state that can be energetically realized and is virtually identical to the crystal structure of one of the analogs. Quantitative structure-activity relationships, QSARs, were separately, and jointly, developed for two series of inhibitors. The distance, D, of a nitrogen atom in the variable heterocycle from the core Cc atom is the most important activity descriptor. The optimum distance between the nitrogen and Cc to maximize inhibitor potency is about 3.6 A for both classes of analogs. Integrated potential energy field difference calculations were also carried out using a proton probe and some of the variable heterocycles. The field calculations coupled with the QSAR studies suggest that the nitrogen 3.6 A from Cc acts as a hydrogen bond acceptor. Two possible three-dimensional pharmacophores are proposed for effective aromatase inhibitors.