MOLECULAR SHAPE AND QSAR ANALYSES OF A FAMILY OF SUBSTITUTED DICHLORODIPHENYL AROMATASE INHIBITORS

Conformational analyses of three families of substituted dichlorodiphe nyl aromatase inhibitors indicated that both potent and weak inhibitor s adopt a common global minimum energy conformation. Further, this glo bal minimum energy conformation is the only meaningful intramolecular conformer state that can be energetically realized and is virtually id entical to the crystal structure of one of the analogs. Quantitative s tructure-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 C-c atom is the most i mportant activity descriptor. The optimum distance between the nitroge n and C-c to maximize inhibitor potency is about 3.6 Angstrom for both classes of analogs. Integrated potential energy field difference calc ulations were also carried out using a proton probe and some of the va riable heterocycles. The field calculations coupled with the QSAR stud ies suggest that the nitrogen 3.6 Angstrom from C-c acts as a hydrogen bond acceptor. Two possible three-dimensional pharmacophores are prop osed for effective aromatase inhibitors.