Structure-guided synthesis of tamoxifen analogs with improved selectivity for the orphan ERRγ

被引：82

作者：

Chao, EYH

Collins, JL

Gaillard, S

Miller, AB

Wang, LP

Orband-Miller, LA

Nolte, RT

McDonnell, DP

Willson, TM

Zuercher, WJ

机构：

[1] GlaxoSmithKline Inc, Discovery Res, Res Triangle Pk, NC 27709 USA

[2] Duke Univ, Levine Sci Res Ctr, Dept Pharmacol & Canc Biol, Durham, NC 27710 USA

来源：

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS | 2006年 / 16卷 / 04期

关键词：

ERR gamma; chemical tool; orphan nuclear receptor;

D O I：

10.1016/j.bmcl.2005.11.030

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

The design and synthesis of 4-hydroxytamoxifen (4-OHT) derivatives are described. The binding affinities of these compounds toward the orphan estrogen-related receptor gamma and the classical estrogen receptor alpha demonstrate that analogs bearing hydroxyalkyl groups display improved binding selectivity profiles compared with that of 4-OHT. An X-ray crystal structure of one of the designed compounds bound to ERR gamma LBD confirms the molecular basis of the selectivity. (c) 2005 Elsevier Ltd. All rights reserved.

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页码：821 / 824

页数：4

相关论文

共 13 条

[1] 4-Hydroxytamoxifen binds to and deactivates the estrogen-related receptor γ [J].

Coward, P ;

Lee, D ;

Hull, MV ;

Lehmann, JM .

PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 2001, 98 (15) :8880-8884

[2] New highly stereoselective synthesis of (Z)-4-Hydroxytamoxifen and (Z)-4-hydroxytoremifene via McMurry reaction [J].

Gauthier, S ;

Mailhot, J ;

Labrie, F .

JOURNAL OF ORGANIC CHEMISTRY, 1996, 61 (11) :3890-3893

[3] To ERR in the estrogen pathway [J].

Giguère, V .

TRENDS IN ENDOCRINOLOGY AND METABOLISM, 2002, 13 (05) :220-225

[4] Structural basis for the deactivation of the estrogen-related receptor γ by diethylstilbestrol or 4-hydroxytamoxifen and determinants of selectivity [J].

Greschik, H ;

Flaig, R ;

Renaud, JP ;

Moras, D .

JOURNAL OF BIOLOGICAL CHEMISTRY, 2004, 279 (32) :33639-33646

[5] CHARGED ANALOGS OF CHLORPROMAZINE AS DOPAMINE ANTAGONISTS [J].

HARROLD, MW ;

CHANG, YA ;

WALLACE, RA ;

FAROOQUI, T ;

WALLACE, LJ ;

URETSKY, N ;

MILLER, DD .

JOURNAL OF MEDICINAL CHEMISTRY, 1987, 30 (09) :1631-1635

[6] PGC-1 and PERC, coactivators of the estrogen receptor-related receptor γ [J].

Hentschke, M ;

Süsens, U ;

Borgmeyer, U .

BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS, 2002, 299 (05) :872-879

[7] Estrogen receptor-related receptors: orphan receptors desperately seeking a ligand [J].

Horard, B ;

Vanacker, JM .

JOURNAL OF MOLECULAR ENDOCRINOLOGY, 2003, 31 (03) :349-357

[8] Peroxisome proliferator-activated receptor coactivator-1α (PGC-1α) coactivates the cardiac-enriched nuclear receptors estrogen-related receptor-α and -γ -: Identification of novel leucine-rich interaction motif within PGC-1α [J].

Huss, JM ;

Kopp, RP ;

Kelly, DP .

JOURNAL OF BIOLOGICAL CHEMISTRY, 2002, 277 (43) :40265-40274

[9] PPARγ coactivator 1β/ERR ligand 1 is an ERR protein ligand, whose expression induces a high-energy expenditure and antagonizes obesity [J].

Kamei, Y ;

Ohizumi, H ;

Fujitani, Y ;

Nemoto, T ;

Tanaka, T ;

Takahashi, N ;

Kawada, T ;

Miyoshi, M ;

Ezaki, O ;

Kakizuka, A .

PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 2003, 100 (21) :12378-12383

[10] The structural basis of estrogen receptor/coactivator recognition and the antagonism of this interaction by tamoxifen [J].

Shiau, AK ;

Barstad, D ;

Loria, PM ;

Cheng, L ;

Kushner, PJ ;

Agard, DA ;

Greene, GL .

CELL, 1998, 95 (07) :927-937