【摘要】 三磷酸腺苷(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.根据326E在药品生产质量管理规范(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8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.更多还原

【Abstract】 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 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.更多还原