Skip to main content
SpringerLink
Log in

Cholesteryl ester transfer protein inhibition by PD 140195

  • Article
  • Published:
Lipids

Abstract

The presence of plasma cholesteryl ester transfer protein (CETP) activity may be atherogenic, and, therefore, strategies to inhibit its activity or production may result in a beneficial effect on lipoprotein profiles and the disease process. The current report describes 4-phenyl-5-tridecyl-4H-1,2,4-triazole-3-thiol (PD 140195), a novel CETP inhibitor. The concentration-dependent inhibition of CETP by PD 140195 and the inhibitory monoclonal antibody (Mab) TP2 is demonstrated in a variety ofin vitro assay systems. Molecular models of PD140195 suggest a spatial mimicry of the cholesteryl ester structure. Despite the structural similarity, kinetic studies with a fluorescent cholesteryl ester analog suggest that the inhibition of transfer is not competitive. PD 140195 also selectively inhibited cholesteryl ester but not triglyceride transfer, while the Mab TP2 blocked CETP transfer of both. Studies were carried out to determine whether CETP inhibition observedin vitro could also be demonstratedin vivo. When PD 140195 was intravenously infused to anesthetized rabbits (up to 20 mg/kg), only transient CETP inhibition was observed.In vitro reconstitution studies in the presence of bovine serum albumin resulted in marked reduction of PD 140195 inhibitory activity. Thus, the low activity of PD 140195 in whole plasma probably results from binding to other plasma proteins.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

Abbreviations

apo:

Apolipoprotein

BODIPY-CE:

cholesteryl 4,4-difluoro-5,7-dimethyl-4-bora-3α,4α-diaza-3-indacenedodecanoate

CETP:

cholesteryl ester transfer protein

DMA/PEG 200:

dimethylacetamide/polyethylene glycol 200

DMSO:

dimethylsulfoxide

DTNB:

5,5′-dithio-bis(2-nitrobenzoic acid)

EBTA:

ethylenediaminetetraacetic acid

FCIA:

fluorescent cholesteryl ester transfer protein inhibition assay

HDL:

high density lipoproteins

HDL3 :

high density lipoproteins isolated between the densities of 1.11–1.21 g/mL

LCAT:

lecithin:cholesterol acyltransferase

LDL:

low density lipoproteins

Mab:

monoclonal antibody

PD 140195:

4-phenyl-5-tridecyl-4H-1,2,4-triazole-3-thiol

VLDL:

very low density lipoprotein

1XDB:

50 mM Tris, 150 mM NaCl, 2mM ethylenediaminetetraacetic acid, pH 7.4 buffer

β-VLDL:

beta migrating very low density lipoproteins

[3H]CL-HDL3 :

high density lipoproteins isolated between the densities of 1.11–1.21 g/mL containing [1,2-3H]cholesteryl linoleate

[3H]TO-HDL3 :

high density lipoproteins isolated between the densities of 1.11–1.21 g/mL containing [9,10-3H]triolein

References

  1. Zilversmit, D.B., Hughes, L.B., and Balmer, J. (1975)Biochim. Biophys. Acta 409, 393–398.

    Article  CAS  PubMed  Google Scholar 

  2. Drayna, D., Jarnagin, A.S., McLean, J., Henzel, W., Kohr, W., Fielding, C., and Lawn, R. (1987)Nature 327, 632–634.

    Article  CAS  PubMed  Google Scholar 

  3. Nagashima, M., McLean, J.W., and Lawn, R.M. (1988)J. Lipid Res. 29, 1643–1649.

    CAS  PubMed  Google Scholar 

  4. Pape, M.E., Rehberg, E.F., Marotti, K.R., and Melchior, G.W. (1991)Arterioscler. Thromb. 11, 1759–1771.

    Article  CAS  PubMed  Google Scholar 

  5. Ha, Y.C., and Barter, P.J. (1982)Comp. Biochem. Physiol. 71B, 265–269.

    CAS  Google Scholar 

  6. Hesler, C.B., Swenson, T.L., and Tall, A.R. (1987)J. Biol. Chem. 262, 2275–2282.

    CAS  PubMed  Google Scholar 

  7. Hesler, C.B., Tall, A.R., Swenson, T.L., Weech, P.K., Marcel, Y.L., and Milne, R.W. (1988)J. Biol. Chem. 263, 5020–5023.

    CAS  PubMed  Google Scholar 

  8. Swenson, T.L., Simmons, J.S., Hesler, C.B., Bisgaier, C., and Tall, A.R. (1987)J. Biol. Chem. 262, 16271–16274.

    CAS  PubMed  Google Scholar 

  9. Swenson, T.L. (1991)Diabetes/Metab. Rev. 7, 139–153.

    Article  CAS  Google Scholar 

  10. Tall, A.R. (1993)J. Lipid Res. 34, 1255–1274.

    CAS  PubMed  Google Scholar 

  11. Mann, C.J., Yen, F.T., Grant, A.M., and Bihain, B.E. (1991)J. Clin. Invest. 88, 2059–2066.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Tall, A., Sammett, D., and Granot, E. (1986)J. Clin. Invest. 77, 1163–1172.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Koizumi, J., Mabuchi, H., Yoshimura, A., Michishita, I., Takeda, M., Itoh, H., Sakai, Y., Sakai, T., Ueda, K., and Takeda, R. (1985)Atherosclersosis 58, 175–186.

    Article  CAS  Google Scholar 

  14. Agellon, L.B., Walsh, A., Hayek, T., Moulin, P., Jiang, X.C., Shelanski, S.A., Breslow, J.L., and Tall, A.R. (1991)J. Biol. Chem. 260, 10796–10801.

    Google Scholar 

  15. Bisgaier, C.L., Siebenkas, M.V., Brown, M.L., Inazu, A., Koizumi, J., Mabuchi, H., and Tall, A.R. (1991)J. Lipid Res. 32, 21–33.

    CAS  PubMed  Google Scholar 

  16. Brown, M.L., Inazu, A., Hesler, C.B., Agellon, L.B., Mann, C., Whitlock, M.E., Marcel, Y.L., Milne, R.W., Koizumi, J. Mabuchi, H., Takeda, R., and Tall, A.R. (1989)Nature 342, 448–451.

    Article  CAS  PubMed  Google Scholar 

  17. Inazu, A., Brown, M.L., Hesler, C.B. Agellon, L.B., Koizumi, J., Takata, K., Maruhama, Y., Mabuchi, H., and Tall, A.R. (1990)N. Engl. J. Med. 323, 1234–1238.

    Article  CAS  PubMed  Google Scholar 

  18. Koizumi, J., Inazu, A., Yagi, K., Koizumi, I., Uno, Y., Kajinami, K., Miyamoto, S., Moulin, P., Tall, A.R., Mabuchi, H., and Takeda, R. (1991)Atherosclerosis 90, 189–196.

    Article  CAS  PubMed  Google Scholar 

  19. Yamashita, S., Hui, D.Y., Wetterau, J.R., Sprecher, D.L., Harmony, J.A.K., Sakai, N., Matsuzawa, Y., and Tarui, S. (1991)Metabolism 40, 756–763.

    Article  CAS  PubMed  Google Scholar 

  20. Hirano, K., Yamashita, S., Funahashi, T., Sakai, N., Menju, M., Ishigami, M., Hiraoka, H., Kameda-Takemura, K., Tokunaga, K., Hoshino, T., Kumasaka, K., Kawano, K., and Matsuzawa, Y. (1993)Atherosclerosis 100, 85–90.

    Article  CAS  PubMed  Google Scholar 

  21. Marotii, K.R., Castle, C.K., Murray, R.W., Rehberg, E.F., Polites, H.G., and Melchior, G.W. (1992)Arterioscler. Thromb. 12, 736–744.

    Article  Google Scholar 

  22. Yamashita, S., Sprecher, D.L., Sakai, N., Matsuzawa, Y., Tarui, S., and Hui, D.Y. (1990)J. Clin. Invest. 86, 688–695.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Ikewaki, K., Sakamoto, T., Rader, D., Schaefer, J., Fairwell, T., Kindt, M., Ishikawa, T., Nagano, M., and Brewer, Jr., H.B. (1991)Arterioscler. Thromb. 11, 1400a.

    Google Scholar 

  24. Inazu, A., Koizumi, J., Mabuchi, H., Kajinami, K., and Takeda, R. (1992)Horm. Metab. Res. 24, 284–288.

    Article  CAS  PubMed  Google Scholar 

  25. Takahashi, K., Jiang, X.-C., Skai, N., Yamashita, S., Hirano, K., Bujo, H., Yamazaki, H., Kusunoki, J., Miura, T., Kussie, P., Matsuzawa, Y., Saito, Y., and Tall, A. (1993)J. Clin. Invest. 92, 2060–2064.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Marotti, K.R., Castle, C.K., Boyle, T.P., Lin, A.H., Murray, R.W., and Melchior, G.W. (1993)Nature 364, 73–75.

    Article  CAS  PubMed  Google Scholar 

  27. Whitlock, M.E., Swenson, T.L., Ramakrishnan, R., Leonard, M.T., Marcel, Y.L., Milne, R.W., and Tall, A.R. (1989)J. Clin. Invest. 84, 129–137.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Abbes, M., and Calvert, G.D. (1989)Biochim. Biophys. Acta 1003, 20–29.

    Article  Google Scholar 

  29. Ha, Y.C., Chang, L.B.F., and Barter, P.J. (1985)Biochim. Biophys. Acta 833, 203–210.

    Article  CAS  PubMed  Google Scholar 

  30. Groener, J.E.M., van Gent, T., and van Tol, A. (1989)Biochim. Biophys. Acta 1002, 93–100.

    Article  CAS  PubMed  Google Scholar 

  31. Wang, S., Deng, L., Milne, R.W., and Tall, A.R. (1992)J. Biol. Chem. 267, 17487–17490.

    CAS  PubMed  Google Scholar 

  32. Morton, R.E., and Zilversmit, D.B. (1981)J. Biol. Chem. 256, 11992–11995.

    CAS  PubMed  Google Scholar 

  33. Warnick, G.R., and Albers, J.J. (1978)J. Lipid Res. 19, 65–76.

    CAS  PubMed  Google Scholar 

  34. Bisgaier, C.L., Minton, L.L., Essenburg, A.D., White, A., and Homan, R. (1993)J. Lipid Res. 34, 1625–1634.

    CAS  PubMed  Google Scholar 

  35. Morton, R.E., and Zilversmit, D.B. (1983)J. Biol. Chem. 258, 11751–11757.

    CAS  PubMed  Google Scholar 

  36. Swenson, T.L., Hesler, C.B., Brown, M.L., Quinet, E., Trotta, P.P., Haslanger, M.F., Gaeta, F.C.A., Marcel, Y.L., Milne, R.W., and Tall, A.R. (1989)J. Biol. Chem. 26, 14318–14326.

    Google Scholar 

  37. Morton, R.E., and Zilversmit, D.B. (1982)J. Lipid Res. 23, 1058–1067.

    CAS  PubMed  Google Scholar 

  38. Busch, S.J., and Harmony, J.A.K. (1990)Lipids 25, 216–220.

    Article  CAS  PubMed  Google Scholar 

  39. Gibson, J.C., Rubinstein, A., and Brown, W.V. (1984)Clin. Chem., 30, 1784–1788.

    CAS  PubMed  Google Scholar 

  40. Jiang, X.C., Masucci-Magoulas, L., Mar, J., Lin, M., Walsh, A., Breslow, J.L., and Tall, A. (1993)J. Biol. Chem. 268, 27406–27412.

    CAS  PubMed  Google Scholar 

  41. Pape, M.E., Ulrich, R.G., Rea, T.J., Marotti, K.R., and Melchoir, G.W. (1991)J. Biol. Chem. 266, 12829–12831.

    CAS  PubMed  Google Scholar 

  42. Rea, T.J., Demattos, R.B., and Pape, M.E. (1993)J. Lipid Res. 34, 1901–1910.

    CAS  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Atherosclerosis Therapeutics, Parke-Davis Pharmaceutical Research, Division of Warner-Lambert Company, 2800 Plymouth Road, 48105, Ann Arbor, Michigan

    Charles L. Bisgaier, Arnold D. Essenburg, Laura L. Minton & Reynold Homan

  2. Department of Chemistry, Parke-Davis Pharmaceutical Research, Division of Warner Lambert Company, 48105, Ann Arbor, Michigan

    C. John Blankley & Andrew White

Authors
  1. Charles L. Bisgaier
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Arnold D. Essenburg
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Laura L. Minton
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Reynold Homan
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. C. John Blankley
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Andrew White
    View author publications

    You can also search for this author in PubMed Google Scholar

About this article

Cite this article

Bisgaier, C.L., Essenburg, A.D., Minton, L.L. et al. Cholesteryl ester transfer protein inhibition by PD 140195. Lipids 29, 811–818 (1994). https://doi.org/10.1007/BF02536247

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/BF02536247

Keywords

Search

Navigation