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Science 23 October 1998:
Vol. 282. no. 5389, pp. 751 - 754
DOI: 10.1126/science.282.5389.751
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Reports

An MTP Inhibitor That Normalizes Atherogenic Lipoprotein Levels in WHHL Rabbits

John R. Wetterau, * Richard E. Gregg, Thomas W. Harrity, Cynthia Arbeeny, dagger Michael Cap, Fergal Connolly, ddagger 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., Scott A. Biller *

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.

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. Logan, C. L. Musial, M. A. Poss, J. A. Robl, L. M. Simpkins, W. A. Slusarchyk, R. Sulsky, P. Taunk, D. R. Magnin, J. A. Tino, R. M. Lawrence, J. K. Dickson Jr., S. A. Biller, Division of Discovery Chemistry, Bristol-Myers Squibb Pharmaceutical Research Institute, Princeton, NJ 08543-4000, USA.
*   To whom correspondence should be addressed. E-mail: Wetterau_John_R{at}msmail.bms.com (J.R.W.) and biller{at}bms.com (S.A.B.)

dagger    Present address: GelTex Pharmacueticals, 9 Fourth Avenue, Waltham, MA 02154, USA.

ddagger    Present address: 14 Royal College of Surgeons, Dublin, Ireland.

§   Present address: Department of Chemistry, 516 Physical Sciences 1, University of California, Irvine, CA 92697, USA.

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Science. ISSN 0036-8075 (print), 1095-9203 (online)