Discovery of Alkyl Conjugated Diene Diacids as Novel ACLY Inhibitors

doi:10.6023/cjoc202405036

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烷基共轭二烯基二酸作为新型ACLY抑制剂的发现

程婷婷^a,b, 宋高磊^a, 成龙^a,b, 王凡^c, 孙新宇^a, 谢治富^a, 张梅^a, 张仰明^d, 李静雅^a,b,c,*, 南发俊^a,b,*

^a中国科学院大学上海药物研究所新药研究国家重点实验室上海 201203;
^b中国科学院大学北京 100049;
^c南京中医药大学中药学院南京 210023;
^d博骥源（上海）生物医药有限公司上海 201203

收稿日期:2024-05-27 修回日期:2024-05-30

Discovery of Alkyl Conjugated Diene Diacids as Novel ACLY Inhibitors

Cheng Tingting^a,b, Song Gaolei^a, Cheng Long^a,b, Wang Fan^c, Sun Xingyu^a, Xie Zhifu^a, Zhang Mei^a, Zhang Yangming^d, Li Jingya^a,b,c,*, Nan Fajun^a,b,*

^aState Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203;
^bUniversity of Chinese Academy of Sciences, Beijing, 100049;
^cSchool of Chinese Materia Medica, Nanjing University of Chinese Medicine, Nanjing, 210023;
^dBurgeon Therapeutics Co., Ltd, Shanghai, 201203, P.R. China

Received:2024-05-27 Revised:2024-05-30
Contact: * E-mail: jyli@simm.ac.cn, fjnan@simm.ac.cn
Supported by:
National Natural Science Foundation of China (82170872); the Medical Guidance Project of Shanghai Science and Technology Commission (20S11903400); Natural Science Foundation of Shanghai's Science and Technology Innovation Action Plan (21ZR1475300).

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Abstract

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, we discovered 326E, 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, we have developed a series of diacids containing conjugated diene based on impurities in manufacturing process of 326E in GMP condition, which represented a unique structural type different from known ACLY inhibitors. Among synthesized all eight possible isomers, compound 43ZZ and 52EE exhibited significant inhibitory effect on de novo lipogenesis and gluconeogenesis in vitro and 43ZZ showed favorable pharmacokinetics. Furthermore, oral administration of 43ZZ and 52EE demonstrated a marked 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.

Key words: Metabolic diseases, ATP-citrate lyase (ACLY), Lipogenesis, ACLY inhibitors, Diene diacids

Cite this article

Cheng Tingting, Song Gaolei, Cheng Long, Wang Fan, Sun Xingyu, Xie Zhifu, Zhang Mei, Zhang Yangming, Li Jingya, Nan Fajun. Discovery of Alkyl Conjugated Diene Diacids as Novel ACLY Inhibitors[J]. Chinese Journal of Organic Chemistry, doi: 10.6023/cjoc202405036.

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烷基共轭二烯基二酸作为新型ACLY抑制剂的发现

Discovery of Alkyl Conjugated Diene Diacids as Novel ACLY Inhibitors

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