FR194738 free base

In intact HepG2 cells, FR194738 concentration-dependently inhibits the incorporation of [ ¹⁴ C]acetate into free cholesterol and cholesteryl ester, with IC ₅₀ s of 4.9 and 8.0 nM, respectively. FR194738 induces intracellular [ ¹⁴ C]squalene accumulation. It increases the incorporation of [ ¹⁴ C]acetate into squalene, an intermediate of cholesterol synthesis. FR194738 potently inhibits squalene epoxidase (SE) in HepG2 cell homogenate and liver microsomes in dogs and rats. The inhibitory effect of FR194738 in comparison to the HMG-CoA reductase inhibitors, Simvastatin, Fluvastatin and Pravastatin, on cholesterol biosynthesis in HepG2 cells is examined. Among these compounds, FR194738 is the most potent, with an IC ₅₀ of 2.1 nM. The IC ₅₀ s of Simvastatin, Fluvastatin and Pravastatin are 40, 28 and 5100 nM, respectively. FR194738 inhibits hamster liver microsomal squalene epoxidase activity in a concentration-dependent manner with an IC ₅₀ of 14 nM.

Serum lipid levels in hamsters after daily administration of FR194738 and Pravastatin for 10 d are measured. FR194738 reduces the serum levels of total, non high density lipoprotein (HDL) and HDL cholesterol, and triglyceride. Treatment of hamsters with FR194738 increases HMG-CoA reductase activity by 1.3-fold at 32 mg/kg compared to the control group and does not significantly change that at 100 mg/kg.

IC50: 9.8 nM (squalene epoxidase, in HepG2 cell homogenates)