Structure-activity studies of non-steroidal aromatase inhibitors: the crystal and molecular structures of CGS 16949A and CGS 18320B.

The crystal and molecular structures of 4-(5,6,7,8-tetrahydroimidazo[1,5-a]pyridin-5-yl)benzonitrile hydrochloride (CGS 16949A) and bis(p-cyanophenyl)imidazo-1-yl methane hemisuccinate (CGS 18320B) have been determined as part of structure-activity relationship studies of non-steroidal aromatase inhibitors. CGS 18320B crystallizes with two inhibitor molecules in the asymmetric unit that are similar in conformation. The cyanophenyl groups and the imidazole moieties in the CGS 18320B molecules display a propellor-like arrangement. The orientation of the imidazole ring in CGS 16949A, which is constrained by the piperidine ring, differs by about 80 degrees from the orientations in both CGS 18320B molecules. The conformations of both compounds are consistent with the proposed model (Banting et al. (1988) J. Enz. Inhibit., 2, 216) for inhibitor binding by positioning of the cyanophenyl group in the steroid A-ring binding site and interaction of the imidazole nitrogen with the iron of the haem.