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An MTP Inhibitor that Normalizes Atherogenic Lipoprotein Levels in WHHL Rabbits

John R. Wetterau, Richard E. Gregg, Thomas W. Harrity, Cynthia Arbeeny, Michael Cap, Fergal Connolly, Ching-Hsuen Chu, Rocco J. George, David A. Gordon, Haris Jamil, Kern G. Jolibois, Lori K. Kunselman, Shih-Jung Lan, Thomas J. Maccagnan, Beverly Ricci, Mujing Yan, Douglas Young, Ying Chen, Olga M. Fryszman, Janette V. H. Logan, Christa L. Musial, Michael A. Poss, Jeffrey A. Robl, Ligaya M. Simpkins, William A. Slusarchyk, Richard Sulsky, Prakash Taunk, David R. Magnin, Joseph A. Tino, R. Michael Lawrence, John K. Dickson Jr. and Scott A. Biller
Science
New Series, Vol. 282, No. 5389 (Oct. 23, 1998), pp. 751-754
Stable URL: http://www.jstor.org/stable/2899269
Page Count: 4
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An MTP Inhibitor that Normalizes Atherogenic Lipoprotein Levels in WHHL Rabbits
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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.

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