Cholesterol-Lowering Effects of BMS-303141 Analogues via Inhibition of Adenosine Triphosphate-Citrate Lyase.

Background: Cholesterol is considered a major factor contributing to cardiovascular diseases. Statins, the most commonly prescribed cholesterol-lowering drugs, are known to have various limitations. Inhibition of Adenosine Triphosphate-Citrate Lyase (ACLY) has been proposed as an alternative therapeutic strategy for managing hypercholesterolemia by lowering cholesterol levels. This has led to the discovery of a cell-permeable small molecule ACLY inhibitor.

Methods: ACLY enzyme activity was assessed using an ACLY Assay Kit with the ADP-Glo Kinase Assay Kit. HepG2 cells were treated with test compounds to demonstrate cholesterol and fatty acid synthesis. Pharmacokinetic studies were performed on CD-1 mice following a single oral dose of the compounds. Hypercholesterolemia was induced in mice through a High-Fat and High Cholesterol Diet (HFHCD), and drugs were administered orally for six weeks. Serum and hepatic lipid profiles were subsequently analyzed.

Results: To increase the pharmacochemical properties, four analogues of BMS-303141, ID0018, ID0023, ID0085, and ID0106, were designed and synthesized. These compounds showed superior ACLY inhibitory activity and dose-dependent suppression of cholesterol and fatty acid synthesis in HepG2 cells. Among the analogues, ID0085 exhibited the most potent ACLY inhibition (IC50: 45 nM, 10-fold lower than BMS- 303141) and achieved near-complete suppression in cholesterol and fatty acid synthesis at the highest concentration. Pharmacokinetic studies revealed improved half-lives and systemic exposures for all analogues. In hypercholesterolemic mouse models, test compounds significantly reduced serum total cholesterol (32.0-57.3%) and low-density lipoprotein cholesterol (67.5-80.2%) levels compared to the vehicle group. Notably, ID0085 also increased high-density lipoprotein cholesterol levels.

Conclusion: Based on the results, ID0085 appears to be the most promising therapeutic candidate for the treatment of hypercholesterolemia.