Discovery of coumarin-based selective aldehyde dehydrogenase 1A1 inhibitors with glucose metabolism improving activity

Liang Dailin; Fan Yazhou; Yang Zhou; Zhang Zhenguo; Liu Meiyang; Liu Li; Jiang Cheng

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Discovery of coumarin-based selective aldehyde dehydrogenase 1A1 inhibitors with glucose metabolism improving activity

机译：基于香豆素的选择性醛脱氢酶1A1抑制剂的发现，葡萄糖代谢改善活性

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Overexpression of aldehyde dehydrogenase 1A1 (ALDH1A1) is associated with the occurrence and development of obesity and insulin resistance. Herein, a series of coumarin-based ALDH1A1 inhibitors were designed, synthesized and evaluated. Among them, compounds 10, 14 and 26 exhibited potent inhibitory activity against ALDH1A1 and high selectivity over ALDH1A2, ALDH1A3, ALDH2 and ALDH3A1. Optimized compound 10 showed markedly improved pharmacokinetic characters and ADME profiles comparing to the lead compound 1. In vitro study demonstrated that 10 alleviated palmitic acid-induced impairment of glucose consumption in HepG2 cells. (C) 2019 Elsevier Masson SAS. All rights reserved.

机译：醛脱氢酶1A1（ALDH1A1）的过度表达与肥胖和胰岛素抵抗的发生和发展有关。在此，设计了一系列基于香豆素的Aldh1A1抑制剂，合成和评估。其中，化合物10,14和26表现出对AlDH1A1的有效抑制活性，并且通过Aldh1a2，Ald1a3，Aldh2和Aldh3a1对高选择性表现出高选择性。优化的化合物10显示出明显改善的药代动力学特性和与铅化合物的ADME谱比较。体外研究表明，10缓解棕榈酸诱导的HepG2细胞中葡萄糖消耗的损害。（c）2019年Elsevier Masson SAS。版权所有。

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来源
《European Journal of Medicinal Chemistry: Chimie Therapeutique》 |2020年第2020期|共12页
作者
Liang Dailin; Fan Yazhou; Yang Zhou; Zhang Zhenguo; Liu Meiyang; Liu Li; Jiang Cheng;
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作者单位

China Pharmaceut Univ Jiang Su Key Lab Drug Design &

Optimizat Tongjiaxiang 24 Nanjing 210009;

China Pharmaceut Univ Key Lab Drug Metab &

Pharmacokinet Tongjiaxiang 24 Nanjing 210009 Peoples;

China Pharmaceut Univ Jiang Su Key Lab Drug Design &

Optimizat Tongjiaxiang 24 Nanjing 210009;

China Pharmaceut Univ Jiang Su Key Lab Drug Design &

Optimizat Tongjiaxiang 24 Nanjing 210009;

China Pharmaceut Univ Dept Med Chem Tongjiaxiang 24 Nanjing 210009 Peoples R China;

China Pharmaceut Univ Key Lab Drug Metab &

Pharmacokinet Tongjiaxiang 24 Nanjing 210009 Peoples;

China Pharmaceut Univ Jiang Su Key Lab Drug Design &

Optimizat Tongjiaxiang 24 Nanjing 210009;

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原文格式 PDF
正文语种 eng
中图分类药学;
关键词
ALDH1A1 inhibitors; Coumarin derivatives; Synthesis; Glucose consumption;

机译：ALDH1A1抑制剂;香豆素衍生物;合成;葡萄糖消费;

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1. Discovery of coumarin-based selective aldehyde dehydrogenase 1A1 inhibitors with glucose metabolism improving activity [J] . Liang Dailin, Fan Yazhou, Yang Zhou, European Journal of Medicinal Chemistry: Chimie Therapeutique . 2020,第期

机译：基于香豆素的选择性醛脱氢酶1A1抑制剂的发现，葡萄糖代谢改善活性
2. Discovery of Orally Bioavailable, Quinoline-Based Aldehyde Dehydrogenase 1A1 (ALDH1A1) Inhibitors with Potent Cellular Activity [J] . Yang Shyh-Ming, Martinez Natalia J., Yasgar Adam, Journal of Medicinal Chemistry . 2018,第11期

机译：发现口服生物的喹啉基醛脱氢酶1A1（ALDH1A1）抑制剂，具有有效的细胞活性
3. Differential Metabolism of Organic Nitrates by Aldehyde Dehydrogenase 1a1 and 2: Substrate Selectivity, Enzyme Inactivation, and Active Cysteine Sites [J] . Pei-Suen Tsou, Nathaniel A. Page, Sean G. Lee, The AAPS Journal . 2011,第4期

机译：醛脱氢酶1a1和2的有机硝酸盐的代谢差异：底物选择性，酶失活和半胱氨酸活性位点。
4. Aldehyde dehydrogenase 2 (ALDH2) polymorphism and metabolism of aldehydes [C] . T. Kawamoto, M. Tsuji, R. Tanaka Annual conference of the International Society of Exposure Science . 2017

机译：醛脱氢酶2（ALDH2）多态性与醛代谢
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7. Discovery of Orally Bioavailable, Quinoline-Based Aldehyde Dehydrogenase 1A1 (ALDH1A1) Inhibitors with Potent Cellular Activity [O] . -1

机译：发现口服生物的喹啉基醛脱氢酶1A1（ALDH1A1）抑制剂，具有有效的细胞活性

Discovery of coumarin-based selective aldehyde dehydrogenase 1A1 inhibitors with glucose metabolism improving activity

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