Discovery of Alkyl Conjugated Diene Diacids as Novel ACLY Inhibitors
文献类型：期刊论文
| 作者 | Cheng, Tingting3,4; Song, Gaolei4; Cheng, Long3,4; Wang, Fan2; Sun, Xinyu4; Xie, Zhifu4; Zhang, Yangming1; Li, Jingya3,4 ; Nan, Fajun3,4
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| 刊名 | CHINESE JOURNAL OF ORGANIC CHEMISTRY
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| 出版日期 | 2024-11-01 |
| 卷号 | 44期号:11页码:3476-3489 |
| 关键词 | metabolic diseases ATP-citrate lyase (ACLY) lipogenesis ACLY inhibitors dienyldicarboxylic acid |
| ISSN号 | 0253-2786 |
| DOI | 10.6023/cjoc202405036 |
| 通讯作者 | Li, Jingya(jyli@simm.ac.cn) ; Nan, Fajun(fjnan@simm.ac.cn) |
| 英文摘要 | Adenosine triphosphate (ATP)-citrate lyase (ACLY) converts cytosolic citrate from the tricarboxylic acid cycle (TCA cycle) into acetyl coenzyme A (acetyl-CoA), which is a building block for cholesterol and fatty acid synthesis. Abnormally high expression of ACLY is associated with multiple metabolic diseases including dyslipidemia, atherosclerosis and non-alcoholic steatohepatitis (NASH), making ACLY an appealing target. In previous work, 326Eb was discovered, featuring an alkenyl dicarboxylic acid scaffold as a novel ACLY inhibitor. 326E can be potentially used to treat hypercholesterolemia and is currently undergoing phase II clinical trials. In this study, a series of diacids containing conjugated diene were developed based on impurities in manufacturing process of 326E in good manufacturing practice of medical products (GMP) condition, which represented a unique structural type different from known ACLY inhibitors. Among synthesized all eight possible isomers, compounds 43ZZ and 52EE exhibited significant inhibitory effect on de novo lipogenesis and gluconeogenesis in vitro reduction of hepatic lipogenesis, along with lowered plasma levels of triglyceride and cholesterol, thereby confirming that these diene diacids as novel ACLY inhibitors have therapeutic potential for hyperlipidemia. |
| WOS关键词 | ATP-CITRATE LYASE ; BEMPEDOIC ACID ; GLUCOSE ; ENZYME |
| 资助项目 | National Natural Science Foundation of China[82170872] ; Medical Guidance Project of Shanghai Science and Technol-ogy Commission[20S11903400] ; Natural Science Foundation of Shanghai Science and Technology Innovation Action Plan[21ZR1475300] |
| WOS研究方向 | Chemistry |
| 语种 | 英语 |
| WOS记录号 | WOS:001378129100019 |
| 出版者 | SCIENCE PRESS |
| 源URL | [http://119.78.100.183/handle/2S10ELR8/315282]  |
| 专题 | 中国科学院上海药物研究所 |
| 通讯作者 | Li, Jingya; Nan, Fajun |
| 作者单位 | 1.Burgeon Therapeut Co Ltd, Shanghai 201203, Peoples R China 2.Nanjing Univ Chinese Med, Sch Chinese Mat Med, Nanjing 210023, Peoples R China 3.Univ Chinese Acad Sci, Beijing 100049, Peoples R China 4.Chinese Acad Sci, Shanghai Inst Mat Med, State Key Lab Drug Res, Shanghai 201203, Peoples R China |
| 推荐引用方式 GB/T 7714 | Cheng, Tingting,Song, Gaolei,Cheng, Long,et al. Discovery of Alkyl Conjugated Diene Diacids as Novel ACLY Inhibitors[J]. CHINESE JOURNAL OF ORGANIC CHEMISTRY,2024,44(11):3476-3489. |
| APA | Cheng, Tingting.,Song, Gaolei.,Cheng, Long.,Wang, Fan.,Sun, Xinyu.,...&Nan, Fajun.(2024).Discovery of Alkyl Conjugated Diene Diacids as Novel ACLY Inhibitors.CHINESE JOURNAL OF ORGANIC CHEMISTRY,44(11),3476-3489. |
| MLA | Cheng, Tingting,et al."Discovery of Alkyl Conjugated Diene Diacids as Novel ACLY Inhibitors".CHINESE JOURNAL OF ORGANIC CHEMISTRY 44.11(2024):3476-3489. |
入库方式： OAI收割
来源：上海药物研究所
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