RPR107393 is an orally active and selective inhibitor of squalene synthase (SQS). It inhibits squalene synthase in rat liver microsomes with an IC50 of 0.8 nM. By increasing cellular farnesol and its derivatives, RPR107393 suppresses fatty acid biosynthesis, thereby reducing triglyceride synthesis. It also lowers plasma cholesterol in rats and marmosets. RPR107393 is applicable in research related to metabolic diseases, such as hypercholesterolemia, hypertriglyceridemia, and atherosclerosis [1][2].

RPR107393 is a potent inhibitor of squalene synthase in rat liver microsomes, with an IC50 ranging from 0.6 to 0.9 nM, and shows no activity towards HMG-CoA reductase (3% inhibition at 1 mM). Within 6 hours, this compound inhibits cholesterol (IC50 = 880 nM) and triglyceride biosynthesis (IC50 = 410 nM) in a concentration-dependent manner in rat hepatocytes. In concentrations of 10 μM (2-24 hours), RPR107393 reduces [1-14 C] acetate incorporation into lipids in a time-dependent manner, with maximal inhibition of cholesterol and triglyceride biosynthesis observed at 2 and 24 hours, respectively. At 1 μM over 4 hours, cholesterol and triglyceride biosynthesis are inhibited by 82.4% and 70.0%, respectively, with the latter effect enhanced by MVL supplementation, indicating a mechanism related to increased FPP derivatives. At concentrations of 1-10 μM over 4 hours, it enhances carnitine-dependent mitochondrial β-oxidation (increasing by 26.5% at 1 μM and 39.5% at 10 μM) and reduces overall triglyceride biosynthesis through a β-oxidation-independent pathway. At 10 μM over 4 hours, RPR107393 inhibits the synthesis of fatty acids and triglycerides in rat hepatocytes by 67.7% and 68.5%, respectively, through inhibition of fatty acid synthesis rather than subsequent metabolic stages, thus reducing triglyceride biosynthesis.

RPR107393, when administered orally at doses of 10, 25, and 30 mg/kg either as a single dose or twice daily for 2-4 days, or once daily for 7 days, demonstrates significant lipid-lowering effects in a rat model. In marmosets, RPR107393 at 20 mg/kg, given either twice daily or once daily for 7 days, selectively reduces low-density lipoprotein cholesterol while maintaining beneficial high-density lipoprotein levels.