Ro 48-8.071, a new 2,3-oxidosqualene:lanosterol cyclase inhibitor lowering plasma cholesterol in hamsters, squirrel monkeys, and minipigs: comparison to simvastatin.

xidosqualene :lanosterol cyclase (OSC, E.C. 5.4.99.7) represents a unique target for a cholesterol lowering drug. Partial inhibition of OSC should reduce synthesis of lanosterol and subsequent sterols, and also stimulate the pro- duction of epoxysterols that repress HMGCoA reductase ex- pression, generating a synergistic, self-limited negative regula- tory loop. Hence, the pharmacological properties of Ro 488071, a new OSC inhibitor, were compared to that of an HMG-CoA reductase inhibitor, simvastatin. Ro 48-8071 blocked human liver OSC and cholesterol synthesis in HepG2 cells in the nanomolar range; in cells it triggered the produc- tion of monooxidosqualene, dioxidosqualene, and epoxycho- lesterol. It was safe in hamsters, squirrel monkeys and at- tingen minipigs at pharmacologically active doses, lowering LDL -60% in hamsters, and at least 30% in the two other species, being at least as efficacious as safe doses of simva- statin. The latter was hepatotoxic in hamsters at doses >30 pmol/kg/day limiting its window of efficacy. Hepatic mono- oxidosqualene increased dose-dependently after treatment with Ro 488071, up to -20 pg/g wet liver or less than 1% of hepatic cholesterol, and it was inversely correlated with LDL levels. Ro 48-8071 did not reduce coenzyme QlO levels in liver and heart of hamsters, and importantly did not trigger an overexpression of hepatic HMG-CoA reductase, squalene syn- thase, and OSC itself. In strong contrast, simvastatin stimu- lated these enzymes dramatically, and reduced coenzyme QlO levels in liver and heart.I Altogether these findings clearly differentiate the OSC inhibitor Ro 488071 from simvastatin, and support the view that OSC is a distinct key component in the regulation of the cholesterol synthesis pathway.- Morand, 0. H., J. D. Aebi, H. Dehmlow, Y-H. Ji, N. Gains, H. Lengsfeld, and J. Himber. Ro 488071, a new 2,Soxido- squalene : lanosterol cyclase inhibitor lowering plasma cho- lesterol in hamsters, squirrel monkeys, and minipigs: com- parison to simvastatin. J. Lipid Res. 1997. 38: 373-390.