Insights of a Lead Optimization Study and Biological Evaluation of Novel 4-Hydroxytamoxifen Analogs as Estrogen-Related Receptor γ (ERRγ) Inverse Agonists

被引：20

作者：

Kim, Jina ^{[1
]}

Woo, Seo Yeon ^{[1
]}

Im, Chun Young ^{[1
]}

Yoo, Eun Kyung ^{[2
]}

Lee, Seungmi ^{[2
]}

Kim, Hyo-Ji ^{[1
]}

Hwang, Hee-Jong ^{[1
]}

Cho, Joong-heui ^{[1
]}

Lee, Won Seok ^{[1
]}

Yoon, Heeseok ^{[1
]}

Kim, Shinae ^{[1
]}

Kwon, Oh-bin ^{[1
]}

Hwang, Hayoung ^{[1
]}

Kim, Krung-Hee ^{[1
]}

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

Singh, Thoudam Debraj ^{[4
]}

Kim, Sang Wook

Hwang, Sung Yeoun ^{[5
]}

Choi, Hueng-Sik ^{[6
]}

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

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

Jeon, Yong Hyun ^{[2
,4
]}

Chin, Jungwook ^{[1
]}

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] Korea Biomed Sci Inst, Seoul 06106, South Korea

[6] Chonnam Natl Univ, Sch Biol Sci & Technol, Natl Creat Res Initiat Ctr, Nucl Receptor Signals & Hormone Res Ctr, Gwangju 61186, South Korea

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

来源：

JOURNAL OF MEDICINAL CHEMISTRY | 2016年 / 59卷 / 22期

基金：

新加坡国家研究基金会;

关键词：

BREAST-CANCER; NUCLEAR RECEPTORS; HEPATIC GLUCONEOGENESIS; TAMOXIFEN RESISTANCE; KEY ROLE; EXPRESSION; IDENTIFICATION; INDUCTION; COACTIVATOR; HOMEOSTASIS;

D O I：

10.1021/acs.jmedchem.6b01204

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

We evaluated the in vitro pharmacology as well as the absorption, distribution, metabolism, excretion, and toxicity (ADMET) properties of chemical entities that not only were shown to be highly selective agonists for ERR gamma but also exhibited enhanced pharmacokinetic profile compared with 3 (GSK5182). 6g and 10b had comparable potency to 3 and were far more selective for ERR gamma over the ERR alpha, -beta, and ER alpha. The in vivo pharmacokinetic profiles of 6g and 10b were further evaluated, as they possessed superior in vitro ADMET profiles compared to the other compounds. Additionally, we observed a significant increase of fully glycosylated NIS protein, key protein for radioiodine therapy in anaplastic thyroid cancer (ATC), in 6g- or 10b treated CAL62 cells, which indicated that these compounds could be promising enhancers for restoring NIS protein function in ATC cells. Thus, 6g and 10b-possess advantageous druglike properties and can be used to potentially treat various ERR gamma-related disorders.

引用

页码：10209 / 10227

页数：19

共 11 条

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