Synthesis and biological evaluation of novel 4-hydroxytamoxifen analogs as estrogen-related receptor gamma inverse agonists

被引：17

作者：

Kim, Jina ^{[1
]}

Chin, Jungwook ^{[1
]}

Im, Chun Young ^{[1
]}

Yoo, Eun Kyung ^{[2
]}

Woo, Seoyeon ^{[1
]}

Hwang, Hee Jong ^{[1
]}

Cho, Joong-heui ^{[1
]}

Seo, Kyung-ah ^{[1
]}

Song, Jaeyoung ^{[1
]}

Hwang, Hayoung ^{[1
]}

Kim, Kyung-Hee ^{[1
]}

Kim, Nam Doo ^{[1
]}

Yoon, Suk Kyoon ^{[1
]}

Jeon, Jae-Han ^{[2
,3
]}

Yoon, Seung-Yun ^{[4
]}

Jeon, Yong Hyun ^{[4
]}

Choi, Hueng-Sik ^{[5
,6
]}

Lee, In-Kyu ^{[2
,3
]}

Kim, Seong Heon ^{[1
,7
]}

Cho, Sung Jin ^{[1
,2
]}

机构：

[1] Daegu Gyeongbuk Med Innovat Fdn, New Drug Dev Ctr, Daegu 41061, South Korea

[2] Kyungpook Natl Univ Hosp, Leading Edge Res Ctr Drug Discovery & Dev Diabet, Daegu 41404, South Korea

[3] Kyungpook Natl Univ, Sch Med, Dept Internal Med, Daegu 41944, South Korea

[4] Kyungpook Natl Univ, Sch Med, Dept Nucl Med, Daegu 41944, South Korea

[5] Chonnam Natl Univ, Natl Creat Res Initiat Ctr Nucl Receptor Signals, Gwangju 61186, South Korea

[6] Chonnam Natl Univ, Hormone Res Ctr, Sch Biol Sci & Technol, Gwangju 61186, South Korea

[7] Boryung R&D Ctr, Chem Res Unit, Gyeonggi Do 15425, South Korea

来源：

EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY | 2016年 / 120卷

基金：

新加坡国家研究基金会;

关键词：

ERR gamma inverse agonist; Nuclear receptor; ADMET; GSK5182; ERR-GAMMA; NUCLEAR RECEPTORS; TRANSCRIPTIONAL FUNCTIONS; HEPATIC GLUCONEOGENESIS; BREAST-CANCER; ALPHA; IDENTIFICATION; REGULATOR; CELLS;

D O I：

10.1016/j.ejmech.2016.04.076

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

Estrogen-related receptor gamma (ERR gamma) has recently been recognized as an attractive target for treating inflammation, cancer, and metabolic disorders. Herein, we discovered and demonstrated the in vitro pharmacology as well as the absorption, distribution, metabolism, excretion, and toxicity (ADMET) properties of chemical entities that could act as highly selective inverse agonists for ERR gamma. The results were comparable to those for GSK5182 (4), a leading ERR gamma inverse agonist ligand. Briefly, the half maximal inhibitory concentration (IC50) range of the synthesized compounds for ERR gamma was 0.1-10 mu M. Impressively, compound 24e exhibited potency comparable to 4 but was more selective for ERR gamma over three other subtypes: ERR alpha, ERR beta, and estrogen receptor alpha. Furthermore, compound 24e exhibited a superior in vitro ADMET profile compared to the other compounds. Thus, the newly synthesized class of ERR gamma inverse agonists could be lead candidates for developing clinical therapies for ERR gamma-related disorders. (C) 2016 Elsevier Masson SAS. All rights reserved.

引用

页码：338 / 352

页数：15

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