RPR101821, A NEW POTENT CHOLESTEROL-LOWERING AGENT - INHIBITION OF SQUALENE SYNTHASE AND 7-DEHYDROCHOLESTEROL REDUCTASE

RPR 101821 (trans-2-[4-(benzoxazol-2-yl)-phenylmethoxy] amino cyclohex ane hydrochloride) is a potent cholesterol-lowering agent in rodents a nd marmoset. The compound inhibited rat liver microsomal squalene synt hase (IC50 = 1 nM) and 7-dehydrocholesterol (7DHC) reductase (IC50 = 1 mu M; Lewis et al. 1995). When RPR 101821 (10 mg/kg), the 7DHC reduct ase inhibitor BM 15.766 (4[2-[4-(4-chlorocinnamyl)piperazine-1-yl]ethy l] benzoic acid; 10 mg/kg) or the HMG-CoA reductase inhibitor lovastat in (30 mg/kg) was given orally to rats at -29 h, -21 h and -5 h, serum cholesterol was reduced by 56%, 46% or 15%, respectively. The reducti on in cholesterol with RPR 101821 was associated with an accumulation of 7DHC in serum, suggesting an inhibition of 7DHC reductase. In the p resence of BM 15.766, RPR 101821 reduced the serum accumulation of 7DH C in a dose-dependent manner, with complete inhibition at 30 mg/kg, p. o. In Balb-cJ mice, RPR 101821 and lovastatin (50 mg/kg, b.i.d., p.o., for 14 days) lowered serum cholesterol by 67% and 2%, respectively. I n marmosets, RPR 101821 and lovastatin (both at a dose of 10 mg/kg, p. o., b.i.d., for 7 days) reduced cholesterol by 28% and 19%, respective ly. In summary, RPR 101821 is an orally effective potent cholesterol-l owering agent in rodents and a small primate species. The suggested me chanism of hypocholesterolemic effect is the inhibition of squalene sy nthase and 7DHC reductase.