An MTP Inhibitor That Normalizes Atherogenic Lipoprotein Levels in WHHL Rabbits
10.1126/science.282.5389.751
Crossref journal-article
American Association for the Advancement of Science (AAAS)
Science (221)
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.

Bibliography

Wetterau, J. R., Gregg, R. E., Harrity, T. W., Arbeeny, C., Cap, M., Connolly, F., Chu, C.-H., George, R. J., Gordon, D. A., Jamil, H., Jolibois, K. G., Kunselman, L. K., Lan, S.-J., Maccagnan, T. J., Ricci, B., Yan, M., Young, D., Chen, Y., Fryszman, O. M., … Biller, S. A. (1998). An MTP Inhibitor That Normalizes Atherogenic Lipoprotein Levels in WHHL Rabbits. Science, 282(5389), 751–754.

Authors 32
  1. John R. Wetterau (first)
  2. Richard E. Gregg (additional)
  3. Thomas W. Harrity (additional)
  4. Cynthia Arbeeny (additional)
  5. Michael Cap (additional)
  6. Fergal Connolly (additional)
  7. Ching-Hsuen Chu (additional)
  8. Rocco J. George (additional)
  9. David A. Gordon (additional)
  10. Haris Jamil (additional)
  11. Kern G. Jolibois (additional)
  12. Lori K. Kunselman (additional)
  13. Shih-Jung Lan (additional)
  14. Thomas J. Maccagnan (additional)
  15. Beverly Ricci (additional)
  16. Mujing Yan (additional)
  17. Douglas Young (additional)
  18. Ying Chen (additional)
  19. Olga M. Fryszman (additional)
  20. Janette V. H. Logan (additional)
  21. Christa L. Musial (additional)
  22. Michael A. Poss (additional)
  23. Jeffrey A. Robl (additional)
  24. Ligaya M. Simpkins (additional)
  25. William A. Slusarchyk (additional)
  26. Richard Sulsky (additional)
  27. Prakash Taunk (additional)
  28. David R. Magnin (additional)
  29. Joseph A. Tino (additional)
  30. R. Michael Lawrence (additional)
  31. John K. Dickson (additional)
  32. Scott A. Biller (additional)
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  14. Plasma chemistries for treatments with vehicle and 1 3 and 6 mg/kg doses of compound 9 were as follows: ALT (U/liter) 73 ± 3 (mean ± SEM) 65 ± 5 75 ± 5 and 71 ± 2 respectively; AST (U/liter) 58 ± 2 45 ± 3 58 ± 2 and 59 ± 3; alkaline phosphatase (U/liter) 131 ± 11 137 ± 1 135 ± 1 and 131 ± 3; lactic dehydrogenase (U/liter) 156 ± 5 136 ± 3 150 ± 3 and 139 ± 5; amylase (U/liter) 1400 ± 300 1600 ± 100 1500 ± 200 and 1700 ± 500; gamma glutamyltransferase (U/liter) 2.3 ± 0.7 2.3 ± 0.2 1.8 ± 0.4 and 2.2 ± 0.5; glucose (mg/dl) 230 ± 7 235 ± 8 194 ± 22 and 199 ± 15; creatinine (mg/dl) 0.4 ± 0 0.4 ± 0 0.4 ± 0 and 0.4 ± 0; blood urea nitrogen (mg/dl) 14 ± 1 14 ± 1 15 ± 1 and 18 ± 2; total protein (g/dl) 5.4 ± 0.1 5.5 ± 0.1 5.7 ± 0.2 and 5.2 ± 0.5; and albumin (g/dl) 3.7 ± 0.1 3.6 ± 0.1 3.6 ± 0.1 and 3.6 ± 0.1.
  15. The milligrams of triglyceride measured per gram of wet weight liver for treatments with vehicle and 1 3 and 6 mg/kg doses of compound 9 were as follows: 9.1 ± 0.6 (mean ± SEM) 11 ± 0.3 18 ± 1.8 and 24 ± 0.4 respectively at 1 week; 8 ± 0.4 11 ± 1.1 12 ± 0.8 and 19 ± 3.4 at 2 weeks; and 9 ± 0.5 11 ± 1.5 23 ± 3.5 and 19 ± 1.0 at 3 weeks.
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  19. The ALT and AST levels of drug-treated rabbits were 54.0 ± 7.4 and 34.6 ± 3.5 U/liter (mean ± SEM) in comparison to vehicle-treated rabbit levels of 48.3 ± 5.2 and 28.8 ± 12.5 U/liter.
Dates
Type When
Created 23 years, 1 month ago (July 27, 2002, 5:50 a.m.)
Deposited 1 year, 7 months ago (Jan. 13, 2024, 12:11 a.m.)
Indexed 1 month, 1 week ago (July 19, 2025, 11:49 p.m.)
Issued 26 years, 10 months ago (Oct. 23, 1998)
Published 26 years, 10 months ago (Oct. 23, 1998)
Published Print 26 years, 10 months ago (Oct. 23, 1998)
Funders 0

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@article{Wetterau_1998, title={An MTP Inhibitor That Normalizes Atherogenic Lipoprotein Levels in WHHL Rabbits}, volume={282}, ISSN={1095-9203}, url={http://dx.doi.org/10.1126/science.282.5389.751}, DOI={10.1126/science.282.5389.751}, number={5389}, journal={Science}, publisher={American Association for the Advancement of Science (AAAS)}, author={Wetterau, John R. and Gregg, Richard E. and Harrity, Thomas W. and Arbeeny, Cynthia and Cap, Michael and Connolly, Fergal and Chu, Ching-Hsuen and George, Rocco J. and Gordon, David A. and Jamil, Haris and Jolibois, Kern G. and Kunselman, Lori K. and Lan, Shih-Jung and Maccagnan, Thomas J. and Ricci, Beverly and Yan, Mujing and Young, Douglas and Chen, Ying and Fryszman, Olga M. and Logan, Janette V. H. and Musial, Christa L. and Poss, Michael A. and Robl, Jeffrey A. and Simpkins, Ligaya M. and Slusarchyk, William A. and Sulsky, Richard and Taunk, Prakash and Magnin, David R. and Tino, Joseph A. and Lawrence, R. Michael and Dickson, John K. and Biller, Scott A.}, year={1998}, month=oct, pages={751–754} }