A short and efficient route to 4-(4-hydroxyphenyl)cycloheptanemethanol was developed, which resulted in the preparation of a mixture of 4 stereoisomers. The stereoisomers were separated by preparative HPLC, and two of the stereoisomers identified by X-ray crystallography. The stereoisomers, as well as a small family of 4-cycloheptylphenol derivatives, were evaluated as estrogen receptor-beta agonists. The lead compound, 4-(4-hydroxyphenyl)cycloheptanemethanol was selective for activating ER relative to seven other nuclear hormone receptors, with 300-fold selectivity for the β over α isoform and with EC50of 30–50 nM in cell-based and direct binding assays.
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Date of publication: 5 September 2018; European Journal of Medicinal Chemistry (vol. 157, pages 791-804)
Author information: K.L. Iresha Sampathi Perera (1); Alicia M. Hanson (2); Sergey Lindeman (1); Andrea Imhoff (2); Xingyun Lu (2); Daniel S. Sem (2); & William A. Donaldson (1)
(1) Department of Chemistry, Marquette University, P. O. Box 1881, Milwaukee, WI, 53201-1881, United States
(2) School of Pharmacy, Center for Structure-based Drug Design and Development, Concordia University Wisconsin, Mequon, WI, 53097, United States