Hydrophobic Interactions Improve Selectivity to ERα for Ben-zothiophene SERMs.

ACS Medicinal Chemistry Letters
Michael J ChalmersJeffrey A Dodge

Abstract

The discovery, pharmacology, and biophysical characterization of an ERα selective benzothiophene (BTPα) is described. BTPα (4) is a high affinity ligand with 140-fold greater selectivity for ERα (K(i)=0.25 nM) over ERbeta (K(i)=35 nM). In rodent models of estrogen action, BTPα blocks the effects of estrogen in the uterus but mimics the effects estrogen on bone. The basis of ERα selectivity for BTPα was evaluated by using protein crystallography and hydrogen/deuterium exchange (HDX) mass spectrometry. HDX data supports that the n-butyl chain of BTPα stabilizes helix 7 in ERα relative to that of ERβ which we propose leads to an enhancement of affinity to the alpha receptor sub-type.

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May 14, 2008·Proceedings of the National Academy of Sciences of the United States of America·Susie Y DaiPatrick R Griffin
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Citations

Aug 28, 2014·International Journal of Environmental Research and Public Health·Hui Wen NgHuixiao Hong
Aug 2, 2018·Pharmaceutics·Indumathi Sathisaran, Sameer Vishvanath Dalvi
Nov 15, 2019·Journal of the American Society for Mass Spectrometry·Alfonso EspadaMichael J Chalmers
Nov 15, 2014·Analytical Chemistry·Gregory F PirroneJohn R Engen
Aug 24, 2021·ACS Omega·Anwesha BhattacharyaSaravanan Peruncheralathan

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