Estrogen receptor-beta (ERβ) is a drug target for memory consolidation in postmenopausal women. Herein is reported a series of potent and selective ERβ agonists (SERBAs) with in vivo efficacy that are A–C estrogens, lacking the B and D estrogen rings. The most potent and selective A–C estrogen is selective for activating ER relative to seven other nuclear hormone receptors, with a surprising 750-fold selectivity for the β over α isoform and with EC50s of 20–30 nM in cell-based and direct binding assays. Comparison of potency in different assays suggests that the ER isoform selectivity is related to the compound’s ability to drive the productive conformational change needed to activate transcription. The compound also shows in vivo efficacy after microinfusion into the dorsal hippocampus and after intraperitoneal injection (0.5 mg/kg) or oral gavage (0.5 mg/kg). This simple yet novel A–C estrogen is selective, brain penetrant, and facilitates memory consolidation.

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Date of publication: 9 May 2018; Journal of Medicinal Chemistry

Author information: Alicia M. Hanson (1); K.L. Iresha Sampathi Perera (2); Jaekyoon Kim (3); Rajesh K. Pandey (2); Noreena Sweeney (1); Xingyun Lu (1); Andra Imhoff (1); Alexander Craig Mackinnon (4); Adam J. Wargolet (5); Rochelle M. Van Hart (5); Karyn M. Frick (3); William A. Donaldson (2); & Daniel S. Sem (1)

(1) Department of Pharmaceutical Sciences, Center for Structure-Based Drug Design and Development, Concordia University Wisconsin, Mequon Wisconsin 53097, United States
(2) Department of Chemistry, Marquette University, P.O. Box 1881, Milwaukee, Wisconsin 53201-1881, United States
(3) Department of Phychology, University of Wisconsin-Milwaukee, 2441 East Hartford Avenue, Milwaukee, Wisconsin 53211, United States
(4) Department of Pathology, Medical College of Wisconsin, 9200 West Wisconsin Avenue, Milwaukee, Wisonsin 53226, United States
(5) Department of Natural Science, Concordia University Wisconsin, Mequon, Wisconsin 53097, United States