title: Effect of ER-27856, a novel squalene synthase inhibitor, on plasma cholesterol in rhesus monkeys: comparison with 3-hydroxy-3-methylglutaryl-coa reductase inhibitors.
abstract: 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 IC(50) 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 ED(50) 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.
authors.affiliation: Eisai Company, Ltd., Tsukuba Research Laboratories, Tsukuba, Ibaraki, Japan.
authors.forename: H
authors.initials: H
authors.lastname: Hiyoshi
authors.forename: M
authors.initials: M
authors.lastname: Yanagimachi
authors.forename: M
authors.initials: M
authors.lastname: Ito
authors.forename: I
authors.initials: I
authors.lastname: Ohtsuka
authors.forename: I
authors.initials: I
authors.lastname: Yoshida
authors.forename: T
authors.initials: T
authors.lastname: Saeki
authors.forename: H
authors.initials: H
authors.lastname: Tanaka
mesh_terms: D000410:Alanine Transaminase / Q000097:blood; D000818:Animals; D000924:Anticholesteremic Agents / Q000494:pharmacology*; D000069059:Atorvastatin; D002784:Cholesterol / Q000097:blood*; D004164:Diphosphonates / Q000009:adverse effects / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D013186:Farnesyl-Diphosphate Farnesyltransferase / Q000037:antagonists & inhibitors*; D006538:Heptanoic Acids / Q000494:pharmacology; D006903:Hydroxymethylglutaryl CoA Reductases / Q000187:drug effects; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology*; D008099:Liver / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D008253:Macaca mulatta; D008297:Male; D008862:Microsomes, Liver / Q000187:drug effects / Q000201:enzymology; D011355:Prodrugs / Q000494:pharmacology; D011758:Pyrroles / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: D000924:Anticholesteremic Agents; D004164:Diphosphonates; C413901:ER 27856; C413900:ER 28448; D006538:Heptanoic Acids; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D011355:Prodrugs; D011758:Pyrroles; D002784:Cholesterol; D000069059:Atorvastatin; D006903:Hydroxymethylglutaryl CoA Reductases; D013186:Farnesyl-Diphosphate Farnesyltransferase; D000410:Alanine Transaminase