piperidines and Hyperlipoproteinemia-Type-II

Topics: Animals; Cholinesterase Inhibitors; Cognition Disorders; Discrimination, Psychological; Disease Models, Animal; Donepezil; Drug Evaluation, Preclinical; Exploratory Behavior; Hyperlipoproteinemia Type II; Indans; Learning; Memory; Mice, Inbred C57BL; Mice, Knockout; Nootropic Agents; Piperidines; Psychological Tests; Receptors, LDL; Space Perception

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.

Topics: Administration, Oral; Animals; Atorvastatin; Cholesterol, HDL; Disease Models, Animal; Enzyme Inhibitors; Farnesyl-Diphosphate Farnesyltransferase; Female; Heptanoic Acids; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Hyperlipoproteinemia Type II; Male; Mice; Mice, Knockout; Oxazepines; Piperidines; Pyrroles; Rabbits; Receptors, LDL; Simvastatin; Species Specificity; Time Factors; Triglycerides

Patients with abetalipoproteinemia, a disease caused by defects in the microsomal triglyceride transfer protein (MTP), do not produce apolipoprotein B-containing lipoproteins. It was hypothesized that small molecule inhibitors of MTP would prevent the assembly and secretion of these atherogenic lipoproteins. To test this hypothesis, two compounds identified in a high-throughput screen for MTP inhibitors were used to direct the synthesis of a highly potent MTP inhibitor. This molecule (compound 9) inhibited the production of lipoprotein particles in rodent models and normalized plasma lipoprotein levels in Watanabe-heritable hyperlipidemic (WHHL) rabbits, which are a model for human homozygous familial hypercholesterolemia. These results suggest that compound 9, or derivatives thereof, has potential applications for the therapeutic lowering of atherogenic lipoprotein levels in humans.

Topics: Alanine Transaminase; Animals; Apolipoproteins B; Aspartate Aminotransferases; Carrier Proteins; Cholesterol; Cricetinae; Disease Models, Animal; Dose-Response Relationship, Drug; Drug Design; Drug Evaluation, Preclinical; Fluorenes; Humans; Hyperlipidemias; Hyperlipoproteinemia Type II; Lipids; Lipoproteins; Liver; Mice; Piperidines; Rabbits; Rats; Triglycerides; Tumor Cells, Cultured