Lipid-lowering effects of TAK-475, a squalene synthase inhibitor, in animal models of familial hypercholesterolemia.
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.
Amano
Yuichiro
Y
Pharmacology Research Laboratories II, Pharmaceutical Research Division, Takeda Chemical Industries, Ltd., 2-17-85, Juso-Honmachi, Osaka 532-8686, Yodogawa, Japan.
Nishimoto
Tomoyuki
T
Tozawa
Ryu ichi
Ri
Ishikawa
Eiichiro
E
Imura
Yoshimi
Y
Sugiyama
Yasuo
Y
D000284:Administration, Oral; D000818:Animals; D000069059:Atorvastatin; D008076:Cholesterol, HDL / Q000097:blood; D004195:Disease Models, Animal; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D013186:Farnesyl-Diphosphate Farnesyltransferase / Q000037:antagonists & inhibitors*; D005260:Female; D006538:Heptanoic Acids / Q000494:pharmacology; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology; D006938:Hyperlipoproteinemia Type II / Q000188:drug therapy*; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D010077:Oxazepines / Q000494:pharmacology*; D010880:Piperidines / Q000494:pharmacology*; D011758:Pyrroles / Q000494:pharmacology; D011817:Rabbits; D011973:Receptors, LDL / Q000235:genetics; D019821:Simvastatin / Q000494:pharmacology; D013045:Species Specificity; D013997:Time Factors; D014280:Triglycerides / Q000097:blood
C466644:1-((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; D008076:Cholesterol, HDL; D004791:Enzyme Inhibitors; D006538:Heptanoic Acids; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D010077:Oxazepines; D010880:Piperidines; D011758:Pyrroles; D011973:Receptors, LDL; D014280:Triglycerides; D000069059:Atorvastatin; D019821:Simvastatin; D013186:Farnesyl-Diphosphate Farnesyltransferase