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Journal of Lipid Research, Vol. 41, 1136-1144, July 2000
Copyright © 2000 by Lipid Research, Inc.

Original Article

Effect of ER-27856, a novel squalene synthase inhibitor, on plasma cholesterol in rhesus monkeys: comparison with 3-hydroxy-3-methylglutaryl-CoA reductase inhibitors

Correspondence to: Hironobu Hiyoshi

Squalene synthase (SQS; EC 2.5.1.21) plays an important role in the cholesterol biosynthetic pathway. We discovered ER-28448, 5-{N-[2-butenyl-3-(2-methoxyphenyl)]-N-methylamino}-1,1-penthylidenebis(phosphonic acid) trisodium salt, as a potent and selective inhibitor of SQS. ER-28448 inhibited SQS in rat liver microsome with an IC₅₀ value of 3.6 nM. We also prepared ER-27856, the tripivaloyloxymethyl ester prodrug of ER-28448. Although less active than ER-28448 in a liver microsome assay, ER-27856 more potently inhibited cholesterol biosynthesis in rat hepatocytes; and ER-27856 orally inhibited de novo cholesterol biosynthesis in Sprague-Dawley rats, with an ED₅₀ value of 1.6 mg/kg. In HepG2 cells, ER-27856 upregulated low density lipoprotein receptor activity to 2.1 times that of control. A time-course study indicated that the inhibitory effect of ER-27856 on cholesterol biosynthesis in rats continued for up to 8 h. In a study of 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors (HMGRIs), atorvastatin actively suppressed cholesterol biosynthesis for 8 h, whereas the effect of pravastatin and simvastatin diminished at 4 and 8 h, respectively. In rhesus monkeys, 4 days of oral administration of ER-27856 lowered plasma total cholesterol (TCHO) more potently than did these HMGRIs. Whereas atorvastatin significantly elevated plasma alanine aminotransferase, a marker of hepatotoxicity, to 3.7 times at 100 mg/kg, ER-27856 increased the level only 1.4 times at 10 mg/kg, at which doses the hypocholesterolemic effect was equivalent. During 28 days of administration, ER-27856 reduced TCHO and non-high density lipoprotein (non-HDL) cholesterol by 72 and 95%, respectively.

These results demonstrate that ER-27856 had more potent hypocholesterolemic activity and less hepatotoxic effect than HMGRIs. ER-27856 may contribute to the treatment of hypercholesterolemic patients.—Hiyoshi, H., M. Yanagimachi, M. Ito, I. Ohtsuka, I. Yoshida, T. Saeki, and H. Tanaka. Effect of ER-27856, a novel squalene synthase inhibitor, on plasma cholesterol in rhesus monkeys: comparison with HMG-CoA reductase inhibitors. J. Lipid Res. 2000. 41: 1136–1144.

Supplementary key words: ER-27856, squalene synthase, HMG-CoA reductase, enzyme inhibition, cholesterol biosynthesis, cholesterol-lowering, rhesus monkeys

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