Open AccessHydrophobic Interactions Improve Selectivity to ERα for Benzothiophene SERMs
Author(s) -
Michael J. Chalmers,
Yong Wang,
Scott Novick,
Masahiko Sato,
Henry U. Bryant,
Chahrzad Montrose-Rafizdeh,
Patrick R. Griffin,
Jeffrey A. Dodge
Publication year - 2012
Publication title -
acs medicinal chemistry letters
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.065
H-Index - 66
ISSN - 1948-5875
DOI - 10.1021/ml2002532
Subject(s) - benzothiophene , selectivity , chemistry , computer science , combinatorial chemistry , organic chemistry , thiophene , catalysis
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.