Hoffmann, R. A wiki for the life sciences where authorship matters. Nature Genetics (2008)

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Chemical Compound Review:

Lecimibide 3-(2,4-difluorophenyl)-1-[5- [(4,5-diphenyl...

Synonyms: SureCN49619, CHEMBL274185, CHEBI:108810, AC1Q4NGD, AR-1L7990, ...

Burnett, J.R. et al., Higley, C.A. et al., Whitman, S.C. et al., Huff, M.W. et al., Wilcox, L.J. et al., et al.

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High impact information on DuP 128

Addition of the acyl coenzyme A:cholesterol acyltransferase inhibitor DuP 128 to cells incubated with the pHA-modified lipoproteins decreased cellular CE by 100%, 82%, and 95%, respectively, but had no effect on cellular triglycerides [1].
In contrast, another ACAT inhibitor, DuP 128 (10 micromol/L), decreased cellular ACAT activity and CE mass by 85% (P<0.002) and 42% (P=0.01), respectively, but had no effect on apoB secretion into media [2].
Mono- and diphenylpyridazine ureido derivatives, structurally related to DuP 128, were synthesized and tested for their inhibitory activity against ACAT isolated from rat liver microsomes [3].
One of the compounds from this series, N'-(2,4-difluorophenyl)-N-[5-[(4,5-diaryl-1H-imidazol-2- yl)thio]pentyl]-N-heptylurea (DuP 128), was selected for development as an intestinally active ACAT inhibitor [4].
We conclude that in miniature pigs fed a high fat, cholesterol containing diet, the inhibition of hepatic cholesteryl ester synthesis by DuP 128 decreases apoB secretion into plasma, but the effect is attenuated relative to a low fat, cholesterol free diet [5].

Biological context of DuP 128

DuP 128 is a potent ACAT inhibitor in vitro and in vivo, inhibiting ACAT in rat hepatic microsomes with an IC50 = 10 nM and possessing potent antihypercholesterolemic activity in vivo [4].

Associations of DuP 128 with other chemical compounds

ACAT inhibitors limit cholesterol absorption in humans; however, the magnitude of the effect, as exemplified by DuP 128, is small [6].
Determination of DuP 128, an ACAT inhibitor and its sulphoxide and sulphone metabolites in human plasma by liquid chromatography [7].
In addition, the concentration of hepatic triglyceride and the activity of diacylglycerol acyltransferase were not altered by DuP 128, indicating a lack of effect of DuP 128 on hepatic triglyceride metabolism [8].

Gene context of DuP 128

In our previous studies, DuP 128 treatment of miniature pigs fed a low fat, cholesterol free diet, decreased VLDL apoB secretion by 65% resulting in a reduction in plasma apoB of 60% [5].

References

Modification of type III VLDL, their remnants, and VLDL from ApoE-knockout mice by p-hydroxyphenylacetaldehyde, a product of myeloperoxidase activity, causes marked cholesteryl ester accumulation in macrophages. Whitman, S.C., Hazen, S.L., Miller, D.B., Hegele, R.A., Heinecke, J.W., Huff, M.W. Arterioscler. Thromb. Vasc. Biol. (1999) [Pubmed]
ApoB100 secretion from HepG2 cells is decreased by the ACAT inhibitor CI-1011: an effect associated with enhanced intracellular degradation of ApoB. Wilcox, L.J., Barrett, P.H., Newton, R.S., Huff, M.W. Arterioscler. Thromb. Vasc. Biol. (1999) [Pubmed]
Mono- or diphenylpyridazines connected to N-(2,4-difluorophenyl)-N'-heptylurea as acyl-CoA:cholesterol acyltransferase inhibitors. Gelain, A., Bettinelli, I., Barlocco, D., Kwon, B.M., Jeong, T.S., Cho, K.H., Toma, L. J. Med. Chem. (2005) [Pubmed]
Acyl CoA:cholesterol acyltransferase (ACAT) inhibitors: synthesis and structure-activity relationship studies of a new series of trisubstituted imidazoles. Higley, C.A., Wilde, R.G., Maduskuie, T.P., Johnson, A.L., Pennev, P., Billheimer, J.T., Robinson, C.S., Gillies, P.J., Wexler, R.R. J. Med. Chem. (1994) [Pubmed]
Inhibition of cholesterol esterification by DuP 128 decreases hepatic apolipoprotein B secretion in vivo: effect of dietary fat and cholesterol. Burnett, J.R., Wilcox, L.J., Telford, D.E., Kleinstiver, S.J., Barrett, P.H., Huff, M.W. Biochim. Biophys. Acta (1998) [Pubmed]
Effect of the acyl-CoA:cholesterol acyltransferase inhibitor DuP 128 on cholesterol absorption and serum cholesterol in humans. Hainer, J.W., Terry, J.G., Connell, J.M., Zyruk, H., Jenkins, R.M., Shand, D.L., Gillies, P.J., Livak, K.J., Hunt, T.L., Crouse, J.R. Clin. Pharmacol. Ther. (1994) [Pubmed]
Determination of DuP 128, an ACAT inhibitor and its sulphoxide and sulphone metabolites in human plasma by liquid chromatography. Lai, C.M., Brogdon, B., Quon, C.Y., Pieniaszek, H.J. Journal of pharmaceutical and biomedical analysis. (1994) [Pubmed]
Inhibition of hepatic ACAT decreases ApoB secretion in miniature pigs fed a cholesterol-free diet. Huff, M.W., Telford, D.E., Barrett, P.H., Billheimer, J.T., Gillies, P.J. Arterioscler. Thromb. (1994) [Pubmed]

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