Analogues of the Potent and Selective ERβ Agonist trans-4-(4-Hydroxyphenyl)cyclohexanemethanol: Synthesis and Evaluation

Subhabrata Chaudhury; Edward A. Wetzel; Mohamed F. Elmansy; Alicia M. Hanson; Sandra Brown-Ford; Alexandra Gleason; K. L. Iresha Sampathi Perera; Daniel S. Sem; William A. Donaldson

doi:10.1055/s-0043-1775444

Synlett, Table of Contents

Synlett
DOI: 10.1055/s-0043-1775444

letter

Small Molecules in Medicinal Chemistry

Analogues of the Potent and Selective ERβ Agonist trans-4-(4-Hydroxyphenyl)cyclohexanemethanol: Synthesis and Evaluation

Subhabrata Chaudhury

^aDepartment of Chemistry, Marquette University, P. O. Box 1881, Milwaukee, WI 53201-1881, USA

,

Edward A. Wetzel

^aDepartment of Chemistry, Marquette University, P. O. Box 1881, Milwaukee, WI 53201-1881, USA

,

Mohamed F. Elmansy

^aDepartment of Chemistry, Marquette University, P. O. Box 1881, Milwaukee, WI 53201-1881, USA

,

Alicia M. Hanson

^bDepartment of Pharmaceutical Sciences, Concordia University Wisconsin, Mequon, WI 53097, USA

,

Sandra Brown-Ford

^bDepartment of Pharmaceutical Sciences, Concordia University Wisconsin, Mequon, WI 53097, USA

,

Alexandra Gleason

^bDepartment of Pharmaceutical Sciences, Concordia University Wisconsin, Mequon, WI 53097, USA

,

K. L. Iresha Sampathi Perera

^aDepartment of Chemistry, Marquette University, P. O. Box 1881, Milwaukee, WI 53201-1881, USA

,

Daniel S. Sem

^bDepartment of Pharmaceutical Sciences, Concordia University Wisconsin, Mequon, WI 53097, USA

,

William A. Donaldson ∗

^aDepartment of Chemistry, Marquette University, P. O. Box 1881, Milwaukee, WI 53201-1881, USA

› Author Affiliations

Abstract

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This manuscript is dedicated to Prof. Russell P. Hughes for his lifetime contributions to organofluorine chemistry.

Abstract

Activation of estrogen receptor-beta (ERβ) has potential benefits for vasomotor symptoms as well as memory consolidation in menopausal women. Ten 4-(4-substituted cyclohexyl)phenols were synthesized and evaluated as ERβ agonists in a TR-FRET ligand displacement assay. Four of the more potent compounds, all of which contained fluoroalkyl groups as the 4-substituent, were further assessed for agonist and antagonist activity in cell-based functional assays for ERβ and ERα. The 4-(4-fluoroalkyl-cyclohexyl)phenols were all >50-fold selective for ERβ over ERα, and none were found to be antagonists for either ERβ or ERα at 7,250 nM. Detection of 200 μM of trans-4-(4-(fluoromethyl)cyclohexyl)phenol in the presence of mouse brain homogenate was possible by ¹⁹F NMR spectroscopy.

Key words

estrogen receptor agonists - phenolic compounds - organofluorine compounds - synthesis

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References

References and Notes
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2 New address: E. A. Wetzel, Debut Biotech, 11545 Sorrento Valley Rd., Suite 310, San Diego, CA 92121
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