Abstract
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.
MeSH terms
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Alanine Transaminase / blood
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Animals
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Apolipoproteins B / blood*
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Aspartate Aminotransferases / blood
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Carrier Proteins / antagonists & inhibitors*
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Cholesterol / blood*
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Cricetinae
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Disease Models, Animal
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Dose-Response Relationship, Drug
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Drug Design
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Drug Evaluation, Preclinical
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Fluorenes / chemistry
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Fluorenes / pharmacokinetics
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Fluorenes / pharmacology*
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Humans
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Hyperlipidemias / blood
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Hyperlipidemias / drug therapy
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Hyperlipoproteinemia Type II / blood*
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Hyperlipoproteinemia Type II / drug therapy
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Lipids / blood
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Lipoproteins / blood
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Liver / metabolism
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Mice
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Piperidines / chemistry
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Piperidines / pharmacokinetics
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Piperidines / pharmacology*
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Rabbits
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Rats
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Triglycerides / blood*
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Triglycerides / metabolism
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Tumor Cells, Cultured
Substances
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9-(((trifluoromethyl)amino)carbonyl)-9-(4-(4-(2-(trifluoromethyl)benzamido)piperidinyl)butyl)fluorene
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Apolipoproteins B
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Carrier Proteins
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Fluorenes
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Lipids
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Lipoproteins
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Piperidines
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Triglycerides
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microsomal triglyceride transfer protein
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Cholesterol
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Aspartate Aminotransferases
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Alanine Transaminase