Lipid-lowering effects of TAK-475, a squalene synthase inhibitor, in animal models of familial hypercholesterolemia.

Abstract

The lipid-lowering effects of 1-[2-[(3R,5S)-1-(3-acetoxy-2,2-dimethylpropyl)-7-chloro-1,2,3,5-tetrahydro-2-oxo-5-(2,3-dimethoxyphenyl)-4,1-benzoxazepine-3-yl] acetyl] piperidin-4-acetic acid (TAK-475), a novel squalene synthase inhibitor, were examined in two models of familial hypercholesterolemia, low-density lipoprotein (LDL) receptor knockout mice and Watanabe heritable hyperlipidemic (WHHL) rabbits. Two weeks of treatment with TAK-475 in a diet admixture (0.02% and 0.07%; approximately 30 and 110 mg/kg/day, respectively) significantly lowered plasma non-high-density lipoprotein (HDL) cholesterol levels by 19% and 41%, respectively, in homozygous LDL receptor knockout mice. The 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors, simvastatin and atorvastatin (in 0.02% and 0.07% admixtures), also reduced plasma levels of non-HDL cholesterol. In homozygous WHHL rabbits, 4 weeks of treatment with TAK-475 (0.27%; approximately 100 mg/kg/day) lowered plasma total cholesterol, triglyceride and phospholipid levels by 17%, 52% and 26%, respectively. In Triton WR-1339-treated rabbits, TAK-475 inhibited to the same extent the rate of secretion from the liver of the cholesterol, triglyceride and phospholipid components of very-low-density lipoprotein (VLDL). These results suggest that the lipid-lowering effects of TAK-475 in WHHL rabbits are based partially on the inhibition of secretion of VLDL from the liver. TAK-475 had no effect on plasma aspartate aminotransferase and alanine aminotransferase activities. Thus, the squalene synthase inhibitor TAK-475 revealed lipid-lowering effects in both LDL receptor knockout mice and WHHL rabbits.

• Authors: Yuichiro Amano, Tomoyuki Nishimoto, Ryu ichi Tozawa, Eiichiro Ishikawa, Yoshimi Imura, Yasuo Sugiyama
• Journal: European journal of pharmacology (Eur J Pharmacol) Vol. 466 Issue 1-2 Pg. 155-61 (Apr 11 2003) ISSN: 0014-2999 [Print] Netherlands
• PMID: 12679152 (Publication Type: Comparative Study, Journal Article)

Chemical References

• 1-((1-(3-acetoxy-2,2-dimethylpropyl)-7-chloro-5-(2,3-dimethoxyphenyl)-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepin-3-yl)acetyl)piperidine-4-acetic acid
• Cholesterol, HDL
• Enzyme Inhibitors
• Heptanoic Acids
• Hydroxymethylglutaryl-CoA Reductase Inhibitors
• Oxazepines
• Piperidines
• Pyrroles
• Receptors, LDL
• Triglycerides
• Atorvastatin
• Simvastatin
• Farnesyl-Diphosphate Farnesyltransferase

Topics

• Administration, Oral
• Animals
• Atorvastatin
• Cholesterol, HDL (blood)
• Disease Models, Animal
• Enzyme Inhibitors (pharmacology)
• Farnesyl-Diphosphate Farnesyltransferase (antagonists & inhibitors)
• Female
• Heptanoic Acids (pharmacology)
• Hydroxymethylglutaryl-CoA Reductase Inhibitors (pharmacology)
• Hyperlipoproteinemia Type II (drug therapy)
• Male
• Mice
• Mice, Knockout
• Oxazepines (pharmacology)
• Piperidines (pharmacology)
• Pyrroles (pharmacology)
• Rabbits
• Receptors, LDL (genetics)
• Simvastatin (pharmacology)
• Species Specificity
• Time Factors
• Triglycerides (blood)