An MTP inhibitor that normalizes atherogenic lipoprotein levels in WHHL rabbits.
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.
Wetterau
J R
JR
Department of Metabolic Diseases, Bristol-Myers Squibb Pharmaceutical Research Institute, Princeton, NJ 08543-4000, USA. Wetterau_John_R@msmail.bms.com
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D000410:Alanine Transaminase / Q000097:blood; D000818:Animals; D001055:Apolipoproteins B / Q000097:blood*; D001219:Aspartate Aminotransferases / Q000097:blood; D002352:Carrier Proteins / Q000037:antagonists & inhibitors*; D002784:Cholesterol / Q000097:blood*; D006224:Cricetinae; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D015195:Drug Design; D004353:Drug Evaluation, Preclinical; D005449:Fluorenes / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D006801:Humans; D006949:Hyperlipidemias / Q000097:blood / Q000188:drug therapy; D006938:Hyperlipoproteinemia Type II / Q000097:blood* / Q000188:drug therapy; D008055:Lipids / Q000097:blood; D008074:Lipoproteins / Q000097:blood; D008099:Liver / Q000378:metabolism; D051379:Mice; D010880:Piperidines / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D011817:Rabbits; D051381:Rats; D014280:Triglycerides / Q000097:blood* / Q000378:metabolism; D014407:Tumor Cells, Cultured
C115225:9-(((trifluoromethyl)amino)carbonyl)-9-(4-(4-(2-(trifluoromethyl)benzamido)piperidinyl)butyl)fluorene; D001055:Apolipoproteins B; D002352:Carrier Proteins; D005449:Fluorenes; D008055:Lipids; D008074:Lipoproteins; D010880:Piperidines; D014280:Triglycerides; C106092:microsomal triglyceride transfer protein; D002784:Cholesterol; D001219:Aspartate Aminotransferases; D000410:Alanine Transaminase