An MTP Inhibitor That Normalizes Atherogenic Lipoprotein Levels in WHHL Rabbits
Author:
Wetterau John R.1, Gregg Richard E.1, Harrity Thomas W.1, Arbeeny Cynthia1, Cap Michael1, Connolly Fergal1, Chu Ching-Hsuen1, George Rocco J.1, Gordon David A.1, Jamil Haris1, Jolibois Kern G.1, Kunselman Lori K.1, Lan Shih-Jung1, Maccagnan Thomas J.1, Ricci Beverly1, Yan Mujing1, Young Douglas1, Chen Ying1, Fryszman Olga M.1, Logan Janette V. H.1, Musial Christa L.1, Poss Michael A.1, Robl Jeffrey A.1, Simpkins Ligaya M.1, Slusarchyk William A.1, Sulsky Richard1, Taunk Prakash1, Magnin David R.1, Tino Joseph A.1, Lawrence R. Michael1, Dickson John K.1, Biller Scott A.1
Affiliation:
1. J. R. Wetterau, R. E. Gregg, T. W. Harrity, C. Arbeeny, M. Cap, F. Connolly, C.-H. Chu, R. J. George, D. A. Gordon, H. Jamil, K. G. Jolibois, L. K. Kunselman, T. J. Maccagnan, B. Ricci, M. Yan, D. Young, Department of Metabolic Diseases, Bristol-Myers Squibb Pharmaceutical Research Institute, Princeton, NJ 08543–4000, USA. S.-J. Lan, Department of Metabolism and Pharmacokinetics, Bristol-Myers Squibb Pharmaceutical Research Institute, Princeton, NJ 08543–4000, USA. Y. Chen, O. M. Fryszman, J. V. H....
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.
Publisher
American Association for the Advancement of Science (AAAS)
Subject
Multidisciplinary
Reference19 articles.
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