烷基共轭二烯基二酸作为新型ACLY抑制剂的发现

doi:10.6023/cjoc202405036

研究论文

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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摘要/Abstract

ATP依赖的柠檬酸裂解酶（ACLY）将三羧酸循环中的细胞质柠檬酸转化为乙酰辅酶A,后者是合成胆固醇和脂肪酸的关键前体。ACLY的异常高表达与多种代谢疾病相关,如血脂异常、动脉粥样硬化和非酒精性脂肪肝炎。这使得ACLY成为一个重要的药物靶标。在前期研究中,我们发现了一种基于烯基二羧酸骨架的新型ACLY抑制剂326E,目前该化合物正处于II期临床试验中,有望用于治疗高胆固醇血症。本研究中,我们根据326E在GMP条件下生产过程中产生的杂质,开发了一系列含有共轭二烯基二羧酸类化合物。这些化合物显示出与已知ACLY抑制剂不同的结构特征。在合成的八种可能的异构体中,化合物43ZZ和52EE在体外实验中显示出显著抑制脂肪生成和糖异生的生物活性,其中43ZZ还表现出良好的药代动力学特性。此外,口服给予43ZZ和52EE能显著降低肝脏脂肪合成,并降低血浆中的甘油三酯和胆固醇水平,证实这些新型二烯基二羧酸类ACLY抑制剂对于治疗高脂血症具有治疗潜力。

关键词: 代谢性疾病, ATP依赖的柠檬酸裂解酶（ACLY）, 脂肪生成, ACLY抑制剂, 二烯二羧酸

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

引用此文

程婷婷, 宋高磊, 成龙, 王凡, 孙新宇, 谢治富, 张梅, 张仰明, 李静雅, 南发俊. 烷基共轭二烯基二酸作为新型ACLY抑制剂的发现[J]. 有机化学, doi: 10.6023/cjoc202405036.

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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