Squalene synthase catalyzes the dimerization of two farnesyl pyrophosphate molecules to form the key cholesterol precursor, squalene. YM-53601 inhibits squalene synthase activity in rat hepatic microsomes and human Hep-G2 cells with IC50 values of 90 and 79 nM, respectively. Cholesterol biosynthesis is inhibited in rats with an ED50 value of 32 mg/kg YM-53601, causing a reduction in both cholesterol and triglyceride levels in plasma. Cholesterol-reducing HMG-CoA reductase inhibitors, which have little effect on plasma triglyceride levels, are often paired with fibrates, which can have adverse effects, to treat hyperlipidemia. The lipid-lowering properties of compounds such as YM-53601 make squalene synthase inhibition an attractive alternative to the combination HMG-CoA reductase inhibitor/fibrate therapy.
