Hypercholesterolaemia remains one of the leading risk factors for the development of cardiovascular disease. Many large double-blind studies have demonstrated that lowering LDL-cholesterol using a statin can reduce the risk of having a cardiovascular event by ~30%. However, despite the success of statins, some patient populations are unable to lower their LDL-cholesterol to meet the targeted lipid levels, due to compliance or potency issues. This is especially true for heterozygous familial hypercholesterolaemia (heFH) patients who may require additional upregulation of the Low-Density Lipoprotein Receptor (LDLR) to reduce LDL-cholesterol levels below those achievable with maximal dosing of statins. Here we identify a series of small molecules from a genomic DNA reporter screen which upregulate the LDLR in mouse and human liver cell lines at nanomolar potencies (EC50: 39 nM). Structure-activity relationship studies carried out on the lead compound (compound OX03771) led to the identification of compound OX03050, which had similar potency (EC50: 26 nM), but a much-improved pharmacokinetic profile and showed in vivo efficacy. Compound OX03050 and OX03771 were found to inhibit squalene synthase, the first committed step in cholesterol biosynthesis. These squalene synthase inhibitors were shown to act cooperatively with statins to increase LDLR expression in vitro. Overall, we have demonstrated here a novel series of small molecules with the potential to be further developed to treat patients either alone, or in combination with statins.
- The American Society for Pharmacology and Experimental Therapeutics