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Chemical Compound Review

CHEMBL22373     2,2-dimethyl-N-(2,4,6- trimethoxyphenyl)dod...

Synonyms: SureCN691688, ACMC-1CUXF, CI-976, AG-D-34501, CHEBI:129382, ...
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Disease relevance of CI 976

  • CI-976 decreased non-high density lipoprotein (HDL)-cholesterol and increased HDL-cholesterol in rats with pre-established dyslipidemia [1].

High impact information on CI 976

  • Inhibition of the Golgi LPAT was achieved by 2,2-dimethyl-N-(2,4,6-trimethoxyphenyl)dodecanamide (CI-976), a previously characterized antagonist of acyl-CoA cholesterol acyltransferase [2].
  • Moreover, preincubation of cells with PLA2 antagonists inhibited the ability of CI-976 to induce tubules [2].
  • Here, we show that CI-976 stimulates tubule formation from all subcompartments of the Golgi complex, and often these tubules formed independently, i.e. individual tubules usually did not contain markers from different subcompartments [3].
  • Tf and TfRs accumulated in centrally located, Rab11-positive vesicles indicating that CI-976 inhibits export of cargo from the central endocytic recycling compartment [3].
  • Previous studies have shown that inhibition of a Golgi-complex-associated lysophospholipid acyltransferase (LPAT) activity by the drug CI-976 stimulates Golgi tubule formation and subsequent redistribution of resident Golgi proteins to the endoplasmic reticulum (ER) [3].

Biological context of CI 976


Anatomical context of CI 976


Associations of CI 976 with other chemical compounds


Gene context of CI 976

  • Finally, CI-976 produced an apparently irreversible block in the endocytic recycling pathway of transferrin (Tf) and Tf receptors (TfRs) but had no direct effect on Tf uptake from the cell surface [3].
  • The combined data strongly supports the hypothesis that orally administered CI-976 inhibits both intestinal and hepatic ACAT, and that both of these enzymes may be determinants of plasma lipid concentrations in the rat [1].
  • Nevertheless, in cholesterol-fed rabbits, both systemically available (7b, 36c) and poorly absorbed inhibitors (1, 36d) were more effective in lowering plasma total cholesterol than the fatty acid amide CI-976 [12].
  • Inhibition of cholesterol esterification in the arterial wall was observed also in a reference group of animals treated with the specific ACAT inhibitor CI-976 [13].
  • A new ACAT inhibitor, PD128042 (CI-976), was first characterized [14].

Analytical, diagnostic and therapeutic context of CI 976


  1. In vivo evidence that the lipid-regulating activity of the ACAT inhibitor CI-976 in rats is due to inhibition of both intestinal and liver ACAT. Krause, B.R., Anderson, M., Bisgaier, C.L., Bocan, T., Bousley, R., DeHart, P., Essenburg, A., Hamelehle, K., Homan, R., Kieft, K. J. Lipid Res. (1993) [Pubmed]
  2. Inhibition of a Golgi complex lysophospholipid acyltransferase induces membrane tubule formation and retrograde trafficking. Drecktrah, D., Chambers, K., Racoosin, E.L., Cluett, E.B., Gucwa, A., Jackson, B., Brown, W.J. Mol. Biol. Cell (2003) [Pubmed]
  3. A unique lysophospholipid acyltransferase (LPAT) antagonist, CI-976, affects secretory and endocytic membrane trafficking pathways. Chambers, K., Judson, B., Brown, W.J. J. Cell. Sci. (2005) [Pubmed]
  4. Hypocholesterolemic activity of a novel inhibitor of cholesterol absorption, SCH 48461. Salisbury, B.G., Davis, H.R., Burrier, R.E., Burnett, D.A., Bowkow, G., Caplen, M.A., Clemmons, A.L., Compton, D.S., Hoos, L.M., McGregor, D.G. Atherosclerosis (1995) [Pubmed]
  5. Acyl-coenzyme A:cholesterol-acyltransferase (ACAT) inhibitors modulate monocyte adhesion to aortic endothelial cells. Saxena, U., Ferguson, E., Newton, R.S. Atherosclerosis (1995) [Pubmed]
  6. Biodisposition studies with the acyl-coenzyme A: cholesterol acyltransferase inhibitor 2,2-dimethyl-N-(2,4,6-trimethoxyphenyl)dodecanamide, CI-976. Woolf, T.F., Black, A., Shum, Y.Y., McNally, W., Lee, H., Chang, T. Drug Metab. Dispos. (1993) [Pubmed]
  7. Inhibitory effect of a new ureidophenol derivative T-2591 on LDL oxidation and ACAT activity. Yasuhara, M., Saito, K., Kubota, H., Ohmizu, H., Suzuki, T. Biol. Pharm. Bull. (1997) [Pubmed]
  8. Tissue specific changes in acyl-CoA: cholesterol acyltransferase (ACAT) mRNA levels in rabbits. Pape, M.E., Schultz, P.A., Rea, T.J., DeMattos, R.B., Kieft, K., Bisgaier, C.L., Newton, R.S., Krause, B.R. J. Lipid Res. (1995) [Pubmed]
  9. Inhibition of acyl-CoA cholesterol O-acyltransferase reduces the cholesteryl ester enrichment of atherosclerotic lesions in the Yucatan micropig. Bocan, T.M., Mueller, S.B., Uhlendorf, P.D., Brown, E.Q., Mazur, M.J., Black, A.E. Atherosclerosis (1993) [Pubmed]
  10. Influence of membrane partitioning on inhibitors of membrane-bound enzymes. Homan, R., Hamelehle, K.L. Journal of pharmaceutical sciences. (2001) [Pubmed]
  11. Acyl-coenzyme A:cholesterol acyltransferase inhibition ameliorates proteinuria, hyperlipidemia, lecithin-cholesterol acyltransferase, SRB-1, and low-denisty lipoprotein receptor deficiencies in nephrotic syndrome. Vaziri, N.D., Liang, K.H. Circulation (2004) [Pubmed]
  12. Inhibitors of acyl-CoA:cholesterol O-acyltransferase. synthesis and pharmacological activity of (+/-)-2-dodecyl-alpha-phenyl-N-(2,4,6-trimethoxyphenyl)-2H-tetrazole-5- acetamide and structurally related tetrazole amide derivatives. O'Brien, P.M., Sliskovic, D.R., Picard, J.A., Lee, H.T., Purchase, C.F., Roth, B.D., White, A.D., Anderson, M., Mueller, S.B., Bocan, T., Bousley, R., Hamelehle, K.L., Homan, R., Lee, P., Krause, B.R., Reindel, J.F., Stanfield, R.L., Turluck, D. J. Med. Chem. (1996) [Pubmed]
  13. Effect of lacidipine on cholesterol esterification: in vivo and in vitro studies. Bernini, F., Canavesi, M., Bernardini, E., Scurati, N., Bellosta, S., Fumagalli, R. Br. J. Pharmacol. (1997) [Pubmed]
  14. Inhibition of acylcoenzyme A: cholesterol acyltransferase activity by PD128O42: effect on cholesterol metabolism and secretion in CaCo-2 cells. Field, F.J., Albright, E., Mathur, S. Lipids (1991) [Pubmed]
  15. Molecular cloning and biochemical characterization of Candida albicans acyl-CoA:sterol acyltransferase, a potential target of antifungal agents. Kim, K.Y., Shin, Y.K., Park, J.C., Kim, J.H., Yang, H., Han, D.M., Paik, Y.K. Biochem. Biophys. Res. Commun. (2004) [Pubmed]
  16. In vitro and in vivo disposition of 2,2-dimethyl-N-(2,4,6-trimethoxyphenyl)dodecanamide (CI-976). Identification of a novel five-carbon cleavage metabolite in rats. Sinz, M.W., Black, A.E., Bjorge, S.M., Holmes, A., Trivedi, B.K., Woolf, T.F. Drug Metab. Dispos. (1997) [Pubmed]
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