RPR-107393, A POTENT SQUALENE SYNTHASE INHIBITOR AND ORALLY EFFECTIVECHOLESTEROL-LOWERING AGENT - COMPARISON WITH INHIBITORS OF HMG-COA REDUCTASE

Squalene synthase catalyzes the reductive dimerization of two molecule s of farnesyl pyrophosphate to form squalene and is the first committe d step in sterol synthesis. A specific inhibitor of squalene synthase would inhibit cholesterol biosynthesis but not prevent the formation o f other products of the isoprenoid pathway, such as dolichol and ubiqu inone. RPR 107393 4-(quinolin-6-yl)phenyl]-1-azabicyclo[2-2-2]octane d ihydrochloride} and its R and S enantiomers are potent inhibitors of r at liver microsomal squalene synthase, with IC50 values of 0.6 to 0.9 nM. One hour after oral administration to rats, RPR 107393 inhibited d e novo [C-14]cholesterol biosynthesis from [C-14]mevalonate in the liv er with an ED50 value of 5 mg/kg, Diacid metabolites of [C-14]farnesyl pyrophosphate were identified after acid treatment of the livers of t hese animals. These results support in vitro data demonstrating that t hese compounds are inhibitors of squalene synthase. In rats, RPR 10739 3 (30 mg/kg p.o. b.i.d. for 2 days) reduced total serum cholesterol by less than or equal to 51%, In the same paradigm, the HMG-CoA reductas e inhibitor lovastatin failed to lower serum cholesterol in rats, In m armosets, RPR 107393 (20 mg/kg b.i.d.) reduced plasma cholesterol conc entration by 50% after 1 week of administration; this was greater than the reduction observed with lovastatin or pravastatin, neither of whi ch produced >31% reduction in plasma cholesterol when administered for 1 week at a dose of 50 mg/kg b.i.d. The R and S enantiomers of RPR 10 7393 (20 mg/kg p.o. q.d. for 7 days) reduced plasma low density lipopr otein cholesterol by 50% and 43%, respectively, whereas high density l ipoprotein cholesterol was unchanged. In summary, RPR 107393 is a pote nt inhibitor of squalene synthase. it is an orally effective hypochole sterolemic agent in rats and marmosets that has greater efficacy than lovastatin or pravastatin in the marmoset.