Inhibitors of Acyl-CoA:cholesterol O-Acyl Transferase (ACAT) as Hypocholesterolemic Agents.6.The First Water-Soluble ACAT Inhibitor with Lipid-Regulating Activity

Sliskovic, Drago R.; Krause, Brian R.; Picard, J. A.; Anderson, Mitchell; Bousley, Richard F.; Hamelehle, Katherine L.; Homan, Reynold; Julian, Thomas N.; Rashidbaigi, Zara A.; Stanfield, R. L.

doi:10.1021/jm00031a002

Cited by 31 publications

(28 citation statements)

References 2 publications

(5 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…However, on the cholesterol-rich diet containing cholate, avasimibe enhanced HDL cholesterol, like other ACAT inhibitors that combine a decrease in non-HDL cholesterol with an increase in HDL cholesterol. 2,48 The cholesterol-fed rats also showed hypertriglyceridemia, which is prevented by avasimibe in agreement with the hepatocyte experiments, in which concomitantly hepatic secretion of cholesteryl esters and triglycerides was decreased. Increases in plasma triglyceride levels in cholesterol-fed rats (HFC/0 diet), counteracted by avasimibe treatment, reflected the accumulation of liver triglycerides, which are known to be related to the mass production and secretion of VLDL-triglyceride.…”

Section: Discussionsupporting

confidence: 77%

“…Recently, a novel class of ACAT inhibitors with improved bioavailability was developed, able to inhibit both intestinal and hepatic ACAT. 2 One of these ACAT inhibitors is avasimibe (CI-1011), ([[2,4,6-tris-(1-ethylethyl) phenyl] acetyl]sulfamic acid, 2,6-bis (1-methyl-ethyl)phenyl ester), which has previously been shown to have cholesterol-lowering activity and to decrease plasma triglyceride levels in animal studies. 3 In addition to the esterification of cholesterol, which leads to its accumulation in tissues and to its secretion in lipoproteins into the circulation, an important cholesterol-metabolizing pathway in the liver is the conversion of cholesterol into bile acids.…”

mentioning

confidence: 99%

See 1 more Smart Citation

Acyl-coenzyme A: Cholesterol acyltransferase inhibitor, avasimibe, stimulates bile acid synthesis and cholesterol 7?-hydroxylase in cultured rat hepatocytes andin vivo in the rat

et al. 1999

View full text Add to dashboard Cite

Acyl-coenzyme A:cholesterol acyltransferase (ACAT) inhibitors are currently in clinical development as potential lipid-lowering and antiatherosclerotic agents. We investigated the effect of avasimibe (Cl-1011), a novel ACAT inhibitor, on bile acid synthesis and cholesterol 7␣-hydroxylase in cultured rat hepatocytes and rats fed different diets. Avasimibe dose-dependently decreased ACAT activity in rat hepatocytes in the presence and absence of ␤-migrating very low-density lipoproteins (␤VLDL) (by 93% and 75% at 10 mol/L) and reduced intracellular storage of cholesteryl esters. Avasimibe (3 mol/L) increased bile acid synthesis (2.9-fold) after preincubation with ␤VLDL and cholesterol 7␣-hydroxylase activity (1.7-and 2.6-fold, with or without ␤VLDL), the latter paralleled by a similar induction of its messenger RNA (mRNA). Hepatocytes treated with avasimibe showed a shift from storage and secretion of cholesteryl esters to conversion of cholesterol into bile acids. In rats fed diets containing different amounts of cholesterol and cholate, avasimibe reduced plasma cholesterol (by 52% to 71%) and triglyceride levels (by 28% to 62%). Avasimibe did not further increase cholesterol 7␣-hydroxylase activity and mRNA in cholesterol-fed rats, but prevented down-regulation by cholate. Avasimibe did not affect sterol 27-hydroxylase and oxysterol 7␣-hydroxylase, 2 enzymes in the alternative pathway in bile acid synthesis. No increase in the ratio of biliary excreted cholesterol to bile acids was found, indicating that ACAT inhibition does not result in a more lithogenic bile. Avasimibe increases bile acid synthesis in cultured hepatocytes by enhancing the supply of free cholesterol both as substrate and inducer of cholesterol 7␣-hydroxylase. These effects may partially explain the potent cholesterol-lowering effects of avasimibe in the rat. (HEPATOLOGY 1999;30:491-500.)

show abstract

Section: Discussionsupporting

confidence: 77%

mentioning

confidence: 99%

Acyl-coenzyme A: Cholesterol acyltransferase inhibitor, avasimibe, stimulates bile acid synthesis and cholesterol 7?-hydroxylase in cultured rat hepatocytes andin vivo in the rat

et al. 1999

View full text Add to dashboard Cite

show abstract

“…For example, for a series of inhibitors evaluated at a selected inhibition level, an aqueous‐faced site would be manifest by variation in Q between inhibitors without changes in D w , whereas a lipid‐faced active site would result in shifts in D w without changes in Q . There is insufficient data in this study to apply this analysis to the identification of the phase that the ACAT inhibitor binding site is exposed to, but, the fact that high lipophilicity is a common feature of ACAT inhibitors8 strongly suggests the approach to the inhibitor binding site on ACAT is from the membrane phase.…”

Section: Discussionmentioning

confidence: 99%

“…Inhibitors of the integral membrane enzyme acyl‐coenzyme A:cholesterol acyltransferase (ACAT), which are typically quite lipophilic,6–8 represent one class of membrane‐active molecules that should be subject to membrane‐partitioning effects and, thus, well suited for analysis by this kinetic method. Evidence of the nonspecific modulation of ACAT inhibitor activity by variations in the membrane phase size that would be expected if membrane‐partition effects were involved has been previously reported 9.…”

Section: Introductionmentioning

confidence: 99%

Influence of membrane partitioning on inhibitors of membrane-bound enzymes

Homan

Hamelehle

2001

Journal of Pharmaceutical Sciences

Self Cite

View full text Add to dashboard Cite

“…Sulfonylurea and its derivatives have caught the attention of medical and agricultural researchers due to their herbicidal [4,5], antihypoglycemic [6,7], anticholesterolemic [8] and antitumour activity [9,10]. In addition, it is known that modified nucleosides and nucleotides reduce the cell mitotic activity resulting in antineoplastic [11][12][13][14][15][16] and antiviral [17] activity.…”

Section: Introductionmentioning

confidence: 99%

In vivo toxicity study of N-1-sulfonylcytosine derivatives and their mechanisms of action in cervical carcinoma cell line

et al. 2011

View full text Add to dashboard Cite

New N-1-sulfonylpyrimidines showed potent growth inhibitory activity against human and mouse tumour cells of different origin. 1-(p-toluenesulfonyl)cytosine (TsC) and 1-(p-toluenesulfonyl)cytosine hydrochloride (TsC × HCl) inhibited the growth of human cervical carcinoma cells (HeLa), and had no significant cytotoxic effects on normal human foreskin fibroblasts (BJ). TsC and TsC × HCl interfered with the HeLa cell cycle progression bringing about the accumulation of G1 phase cells and the induction of apoptosis. Antiproliferative effects of TsC and TsC × HCl were additionally confirmed by investigating de novo synthesis of RNA, DNA and proteins in HeLa cells. Monitoring gene expression using DNA Chip Analysis and quantitative PCR showed that TsC × HCl affects the expression of several cell-cycle regulating genes implying that cell cycle arrest and DNA damage-induced apoptosis might account for the observed cellular effects. In vivo experiments revealed low toxicity of TsC × HCl, as demonstrated by unaltered haematological and metabolic blood parameters. In conclusion, potent antitumour efficacy and low toxicity of new compounds in comparison with the common chemotherapy drug 5-FU make them promising anticancer agents. Additional pre-clinical and clinical studies are warranted to illuminate the mode of action of these newly synthesized compounds in vivo, which would lay the groundwork for their further optimization.

show abstract

Inhibitors of Acyl-CoA:cholesterol O-Acyl Transferase (ACAT) as Hypocholesterolemic Agents.6.The First Water-Soluble ACAT Inhibitor with Lipid-Regulating Activity

Cited by 31 publications

References 2 publications

Acyl-coenzyme A: Cholesterol acyltransferase inhibitor, avasimibe, stimulates bile acid synthesis and cholesterol 7?-hydroxylase in cultured rat hepatocytes andin vivo in the rat

Acyl-coenzyme A: Cholesterol acyltransferase inhibitor, avasimibe, stimulates bile acid synthesis and cholesterol 7?-hydroxylase in cultured rat hepatocytes andin vivo in the rat

Influence of membrane partitioning on inhibitors of membrane-bound enzymes

In vivo toxicity study of N-1-sulfonylcytosine derivatives and their mechanisms of action in cervical carcinoma cell line

Contact Info

Product

Resources

About