Design, Synthesis, and Structure-Activity Relationship Studies for a New Imidazole Series of J774 Macrophage Specific Acyl-CoA:Cholesterol Acyltransferase (ACAT) Inhibitors

Tp, Maduskuie; Rg, Wilde; Jt, Billheimer; Da, Cromley; Germain, Sandie J.; Pj, Gillies; Ca, Higley; Al, Johnson; Pennev, P.; Ej, Shimshick

doi:10.1021/jm00007a004

Cited by 35 publications

(18 citation statements)

References 12 publications

(4 reference statements)

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“…Cholesterol ester stores were markedly reduced in adrenal cortices and cultured peritoneal macrophages; however, substantial levels of ACAT activity were present in Acact Ϫ/Ϫ livers, and intestinal cholesterol absorption was normal, indicating that another ACAT was active in these tissues (15). Studies examining the tissue distribution of Acact mRNA expression also supported the hypothesis that more than one ACAT exists (16), as did previous biochemical (17) and ACAT inhibitor (18) studies showing differences between liver and aorta/macrophage ACAT activities. Taken together, these data led us to hypothesize that a second ACAT contributes to cholesterol esterification activity in the liver and small intestine.…”

mentioning

confidence: 52%

ACAT-2, A Second Mammalian Acyl-CoA:Cholesterol Acyltransferase

Cases¹,

Novak²,

Zheng³

et al. 1998

Journal of Biological Chemistry

359

262

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The synthesis of cholesterol esters by acyl-CoA:cholesterol acyltransferase (ACAT, EC 2.3.1.26) is an important component of cellular cholesterol homeostasis. Cholesterol ester formation also is hypothesized to be important in several physiologic processes, including intestinal cholesterol absorption, hepatic lipoprotein production, and macrophage foam cell formation in atherosclerotic lesions. Mouse tissue expression studies and the disruption of the mouse ACAT gene (Acact) have indicated that more than one ACAT exists in mammals and specifically that another enzyme is important in mouse liver and intestine. We now describe a second mammalian ACAT enzyme, designated ACAT-2, that is 44% identical to the first cloned mouse ACAT (henceforth designated ACAT-1). Infection of H5 insect cells with an ACAT-2 recombinant baculovirus resulted in expression of a ϳ46-kDa protein in cell membranes that was associated with high levels of cholesterol esterification activity. Both ACAT-1 and ACAT-2 also catalyzed the esterification of the 3␤-hydroxyl group of a variety of oxysterols. Cholesterol esterification activities for ACAT-1 and ACAT-2 exhibited different IC 50 values when assayed in the presence of several ACAT-specific inhibitors, demonstrating that ACAT inhibitors can selectively target specific forms of ACAT. ACAT-2 was expressed primarily in mouse liver and small intestine, supporting the hypothesis that ACAT-2 contributes to cholesterol esterification in these tissues. The mouse ACAT-2 gene (Acact2) maps to chromosome 15 in a region containing a quantitative trait locus influencing plasma cholesterol levels. The identification and cloning of ACAT-2 will facilitate molecular approaches to understanding the role of ACAT enzymes in mammalian biology.

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mentioning

confidence: 52%

ACAT-2, A Second Mammalian Acyl-CoA:Cholesterol Acyltransferase

Cases¹,

Novak²,

Zheng³

et al. 1998

Journal of Biological Chemistry

359

262

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“…28,62 DuP 128 is a lipophilic, noncompetitive ACAT inhibitor with limited oral bioavailability 23 and an in vitro IC 50 of 10 nmol/L for rat liver microsomal ACAT activity. 63,64 In contrast, CI-1011, is an acyl sulfamate with quite different physiochemical properties compared with the more lipophilic, typical ACAT inhibitors. 28 CI-1011 has a high IC 50 , ranging from 12 mol/L to 60 nmol/L depending on ACAT assay conditions.…”

Section: Discussionmentioning

confidence: 99%

ApoB100 Secretion From HepG2 Cells is Decreased by the ACAT Inhibitor CI-1011

Wilcox

Barrett

Newton

et al. 1999

ATVB

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Abstract-The concept that hepatic cholesteryl ester (CE) mass and the rate of cholesterol esterification regulate hepatocyte assembly and secretion of apoB-containing lipoproteins remains controversial. The present study was carried out in HepG2 cells to correlate the rate of cholesterol esterification and CE mass with apoB secretion by CI-1011, an acyl CoA:cholesterol acyltransferase (ACAT) inhibitor that is known to decrease apoB secretion, in vivo, in miniature pigs. HepG2 cells were incubated with CI-1011 (10 nmol/L, 1 mol/L, and 10 mol/L) for 24 hours. ApoB secretion into media was decreased by 25%, 27%, and 43%, respectively (PϽ0.0012). CI-1011 (10 mol/L) inhibited HepG2 cell ACAT activity by 79% (PϽ0.002) and cellular CE mass by 32% (PϽ0.05). In contrast, another ACAT inhibitor, DuP 128 (10 mol/L), decreased cellular ACAT activity and CE mass by 85% (PϽ0.002) and 42% (Pϭ0.01), respectively, but had no effect on apoB secretion into media. To characterize the reduction in apoB secretion by CI-1011, pulse-chase experiments were performed and analyzed by multicompartmental modelling using SAAM II. CI-1011 did not affect the synthesis of apoB or albumin. However, apoB secretion into the media was decreased by 42% (Pϭ0.019). Intracellular apoB degradation increased proportionately (Pϭ0.019). A poB100, synthesized in the liver, is an essential structural component of VLDL and its metabolic products, IDL and LDL. 1,2 ApoB is required for the intracellular assembly and secretion of these lipoproteins, and serves as a ligand for LDL receptor-mediated clearance of these particles from the plasma. 3 Hepatic overproduction of apoB-containing lipoproteins is a major risk factor for atherosclerosis. Therefore, studies designed to understand the processes regulating apoB assembly and secretion from hepatocytes are important. The production of these lipoproteins is complex and requires the coordinated synthesis and assembly of apoB, triglyceride (TG), free and esterified cholesterol (FC; cholesteryl ester, CE), phospholipids (PLs), and other components. Although considerable progress has been made in understanding these processes, many questions remain unresolved.ApoB is thought to be regulated primarily at posttranscriptional levels. The rates of apoB translocation across the endoplasmic reticulum (ER) membrane and intracellular degradation are believed to regulate the amount of apoBcontaining lipoproteins secreted from the liver. 4,5 Therefore, the secretion rate of apoB results from the proportion of newly synthesized apoB molecules that associate with lipid and move through the secretory pathway, versus the proportion that are degraded within the cell shortly after, or during, their synthesis. Although hepatic regulation of apoB secretion is generally considered to occur posttranslationally, transcriptional regulation may also play a minor role. Increased delivery of 25-hydroxycholesterol 6 or VLDL 7 to cultured hepatocytes has been shown to affect mRNA levels and secretion efficiency of apoB.Several factors have been...

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“…They can be formed from a-bromoketones with substituted hydrazines and potassium thiocyanate (Lagoja et al, 2003), from a-hydroxyketones, thiourea and ammonium thiocyanate (Maduskuie et al, 1995), from benzil and thiourea (Muccioli et al, 2006), from phenylglycine methyl ester with phenyl or alkyl isothiocynate (Muccioli et al, 2006) and from diamines and CS 2 over a zinc oxide/aluminium oxide catalyst (Ballabeni et al, 1999) to name a few. The imidazole-2-thiones are extremely reactive and can be alkylated and arylated at both sulphur and nitrogen using a variety of reagents (Trzhtsinskaya and Abramova, 1991), added to activated double bonds such as 2-cyanoethene (Bagrii and Vasilenko, 1978;Trzhtsinskaya et al, 1992), acetylene (Skvortsova et al, 1974), aliphatic and alicyclic ketones and acetophenones (Hozien et al, 2000).…”

Section: Introductionmentioning

confidence: 99%

“…They were also shown to possess anti-HIV activity, by showing non-nucleoside reverse transcriptase inhibition (Yasser et al, 2003) and human cytosolic phospholipase A2 activity having a role in preventing inflammation (Makita et al, 2000). They are known to be Acyl-CoA:Cholesterol acyltransferase (ACAT) inhibitors, limiting the absorption of dietary cholesterol (Maduskuie et al, 1995), protein kinase inhibitors responsible for preventing the gene expression of proinflammatory cytokines (Buhler et al, 2011), anti-hypercholesteremics (Billheimer et al, 1990) and platelet aggregation inhibitors (Hayashi et al, 1989). Platelet aggregation inhibitors play a crucial role in the prevention of aberrant platelet activation and aggregation which could lead to serious cardiovascular events.…”

Section: Introductionmentioning

confidence: 99%

Synthesis and in vitro antiplatelet aggregation screening of novel fluorinated diethyl-2-(benzylthio)-2,3-dihydro-1H-imidazole-4,5-dicarboxylate derivatives

et al. 2014

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Seven fluorinated derivatives of diethyl-2-(benzylthio)-2,3-dihydro-1H-imidazole-4,5-dicarboxylate (a-g) as well as a nitro and chloro derivative (h-i) were prepared in five steps from glycine, ethyl formate, diethyl oxalate, potassium thiocyanate and substituted benzyl bromides. The structures of the synthesised compounds were elucidated and verified using 1 H, 13 C and 2D NMR spectroscopy where appropriate. The synthesised compounds exhibited concentration dependent antiplatelet aggregation activity on both the thrombin and ADP-induced platelet aggregation. The 4-nitro and 4-fluoro compounds exhibited the highest activity from the compounds tested, with IC 50 values of 1.06 and 1.20 mM for the thrombininduced assay and 18.57 and 12.91 mM in the ADP-induced platelet aggregation assay respectively. Three of the compounds, the 3 00 ,4 00 -difluoro (6c), 4 00 -nitro (6h) and 3 00 -chloro (6i) derivatives, have reasonable activity in both of the assays and could have potential as broad spectrum antiplatelet inhibitors. With the exception of 6c, the fluoro derivatives were not as active as the nitro and chloro compounds.

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Design, Synthesis, and Structure-Activity Relationship Studies for a New Imidazole Series of J774 Macrophage Specific Acyl-CoA:Cholesterol Acyltransferase (ACAT) Inhibitors

Cited by 35 publications

References 12 publications

ACAT-2, A Second Mammalian Acyl-CoA:Cholesterol Acyltransferase

ACAT-2, A Second Mammalian Acyl-CoA:Cholesterol Acyltransferase

ApoB100 Secretion From HepG2 Cells is Decreased by the ACAT Inhibitor CI-1011

Synthesis and in vitro antiplatelet aggregation screening of novel fluorinated diethyl-2-(benzylthio)-2,3-dihydro-1H-imidazole-4,5-dicarboxylate derivatives

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