Hydrophobic Interactions Improve Selectivity to ERα for Benzothiophene SERMs

被引：14

作者：

Chalmers, Michael J. ^{[2
]}

Wang, Yong ^{[1
]}

Novick, Scott ^{[2
]}

Sato, Masahiko ^{[1
]}

Bryant, Henry U. ^{[1
]}

Montrose-Rafizdeh, Chahrzad ^{[1
]}

Griffin, Patrick R. ^{[2
]}

Dodge, Jeffrey A. ^{[1
]}

机构：

[1] Eli Lilly & Co, Lilly Res Labs, Indianapolis, IN 46285 USA

[2] Scripps Res Inst, Dept Mol Therapeut, Jupiter, FL 33458 USA

来源：

ACS MEDICINAL CHEMISTRY LETTERS | 2012年 / 3卷 / 03期

关键词：

estrogen receptor alpha; estrogen receptor beta; SERM; hydrogen/deuterium exchange; ESTROGEN-RECEPTOR MODULATORS; MULTIFUNCTIONAL MEDICINES; ANTIESTROGENS; BETA;

D O I：

10.1021/ml2002532

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

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

引用

页码：207 / 210

页数：4

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