Aromatase Inhibitors : Synthesis, Biological Activity, and Structure of 1, 2-Imidazolylmethylcyclopentanol Derivatives

Abstract

Two series of 1, 2-disubstituted imidazolylmethylcyclopentanol derivatives (5a-d, 10a-d) were prepared by using easily available metyl 2-oxocyclopentanecarboxylate as the starting material. Evaluation of the aromatase inhibitory activities in vitro was performed. Their activities were compared with those of a steroidal aromatase inhibitor, Formestane, and a non-steroidal inhibitor, Fadrozole. Among these compounds, the aromatase inhibitory activities of 5d, 10a, 10b, 10c, 11a, 15a, and 15b were more potent than Formestane. One compound, 1-(4-chlorobenzyl)-cis-2-(1H-imidazol-1-ylmethyl)cyclopentanol (10a) was in particular identified as a potent aromatase inhibitor in vitro, exhibiting an IC₅₀ value of 4×10^-8M. The enantiomers of 10a were separated, and their absolute configurations were determined by X-ray crystallography.