Substituted (1,2-Diarylethyl)amide Acyl-CoA:Cholesterol Acyltransferase Inhibitors: Effect of Polar Groups on in Vitro and in Vivo Activity

Clader, John W.; Berger, Joel G.; Burrier, Robert E.; Davis, Harry R.; Domalski, Martin S.; Dugar, Sundeep; Kogan, Timothy P.; Salisbury, Brian; Vaccaro, Wayne

doi:10.1021/jm00010a004

Cited by 24 publications

(22 citation statements)

References 6 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…As shown in Fig. 2, Sah 58-035 inhibited ACAT with an IC 50 of 0.38 Ϯ 0.12 M, similar to that reported in the literature (Clader et al, 1995). Tamoxifen inhibited in a concentration-dependent manner ACAT with an IC 50 of 6.74 Ϯ 0.84 M (Fig.…”

Section: Resultssupporting

confidence: 88%

Tamoxifen Is a Potent Inhibitor of Cholesterol Esterification and Prevents the Formation of Foam Cells

Médina

Payré²,

Bernad³

et al. 2003

J Pharmacol Exp Ther

View full text Add to dashboard Cite

Tamoxifen is a selective estrogen receptor modulator (SERM) used for the treatment and prevention of breast cancer. Tamoxifen has been reported to protect against the progression of coronary artery diseases in human and different atherosclerosis animal models by blocking the appearance of the atheromatous plaque. However, the molecular mechanism of this effect remains unknown. Acyl-CoA:cholesterol acyl transferase (ACAT) catalyzes the biosynthesis of cholesteryl esters, which are the major lipids found in the atheromatous plaque. In this paper we have tested whether ACAT might be inhibited by tamoxifen. We show, using molecular modeling, that tamoxifen displays three-dimensional structural homology with Sah 58-035 (3-[decyldimethylsilyl]-N-[2-(4-methylphenyl)-1-phenylethyl]-propanamide), a prototypical inhibitor of ACAT. We report that tamoxifen inhibits ACAT in a concentration-dependent manner on rat liver microsomal extract. We show that the presence on estrogen receptor ligands of a backbone isosteric to the diphenyl ethane backbone of Sah 58-035 constitutes a pharmacophore for ACAT inhibition. More importantly, tamoxifen was able to inhibit ACAT on intact macrophages stimulated with acetylated low-density lipoproteins and blocked the formation of foam cells, a step that precedes the formation of the atheromatous plaque. This work constitutes the first evidence that tamoxifen is an inhibitor of ACAT and foam cell formation at therapeutic doses and that this may account for its atheroprotective action.

show abstract

Section: Resultssupporting

confidence: 88%

Tamoxifen Is a Potent Inhibitor of Cholesterol Esterification and Prevents the Formation of Foam Cells

Médina

Payré²,

Bernad³

et al. 2003

J Pharmacol Exp Ther

View full text Add to dashboard Cite

show abstract

“…At 10 μM, SR144528 and AM-251 inhibited ACAT activities ~68% and ~77%, respectively. In comparison, 58–035 inhibited ACAT with an IC 50 of 0.4 ± 0.2 μM, similar to that reported in the literature [19]. …”

Section: Resultssupporting

confidence: 89%

AM-251 and SR144528 are acyl CoA:cholesterol acyltransferase inhibitors

Thewke

Freeman-Anderson

Pickle

et al. 2009

Biochemical and Biophysical Research Communications

View full text Add to dashboard Cite

Oxysterol-induced macrophage apoptosis may have a role in atherosclerosis. Macrophages lacking the type 2 cannabinoid receptor (CB2) are partially resistant to apoptosis induced by 7-ketocholesterol (7KC). AM-251 and SR144528 are selective antagonists of CB1 and CB2 receptors, respectively. We observed that both compounds reduce 7KC-induced apoptosis in Raw 264.7 macrophages. As oxysterol-induced macrophage apoptosis requires acyl-coenzymeA:cholesterol acyltransferase (ACAT) activity, we tested their affects on ACAT activity. AM-251 and SR144528 both reduced cholesteryl ester synthesis in unstimulated and acetylated LDL-stimulated Raw 264.7 macrophages, CB2 +/+ and CB2 −/− peritoneal macrophages, as well as in vitro, in mouse liver microsomes. Consistent with inhibition of ACAT, the development of foam cell characteristics in macrophages by treatment with acetylated LDL was reduced by both compounds. This work is the first evidence that AM-251 and SR144528 are inhibitors of ACAT and as a result, might have antiatherosclerotic activities independent of their affect on cannabinoid signaling. Keywords 7-ketocholesterol; ACAT; apoptosisDuring atherogenesis, macrophages in the vascular intima take up modified low density lipoproteins (LDL), such as oxidized LDL (OxLDL), and store much of the LDL-derived cholesterol as cholesteryl esters in cytosolic lipid droplets [1]. Accumulation of cytosolic lipid droplets within macrophages transforms them into the foam cells which define early atherosclerotic lesions known as fatty streaks [2]. Intracellular cholesteryl ester synthesis is carried out by acyl-coenzyme A:cholesterol acyltransferase (ACAT) using cholesterol and fatty-acyl CoA as substrates [3]. Inhibition of ACAT prevents foam cell formation and, in some animal studies, slows the progression of atherosclerosis [4].Lesional macrophage apoptosis plays several roles during the pathophysiology of atherosclerosis. During early lesion formation, macrophage apoptosis is anti-atherosclerotic [5,6] while at later stages it likely contributes to plaque destabilization [7]. Lesional macrophages are subject to several apoptotic inducers, including oxLDL, which potently induces apoptosis in cultured macrophages largely as a result of its cytotoxic oxysterol *Corresponding author: Phone: 423-439-2131, Fax: 423-439-2130, Email: Thewke@etsu.edu. Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. [8,9]. Oxysterols are also substrates for ACAT and reduction of ACAT activity in macrophages produces resistance to 7KC-induced apoptosis, indicating that ACAT is a required step in the signal...

show abstract

“…[11] Some authors used a reaction of 4-substituted (chloro or nitro) anilines with benzoyl chlorides in the presence of zinc chloride under drastic conditions (heating at 200 to 2308C). [8] The Friedel -Crafts acylation of activated benzene rings with various acylating agents such as benzamide, benzonitrile, ethyl benzoate, and benzoic acid in the presence of polyphosphoric acid (PPA) is the most used method for direct synthesis of aromatic ketones. [7,12] In a search of a new approach to isoquinolines we investigated the reaction of carboxylic acids, their esters, and anhydrides with 2-(3,4-dimethoxyphenyl)-ethylamine (homoveratrylamine) and its derivatives in PPA.…”

Section: Resultsmentioning

confidence: 99%

“…[7] 2-(4-Aminophenyl)-1-phenyl-ethanone also possess in vivo and in vitro activity as inhibitor of acyl-CoA-cholesterol acyltransferase (ACAT). [8] Besides benzophenones were intermediates in the synthesis of benzodiazepine derivatives [9] and were investigated in the research laboratories of Hoffman-La Roche. [10] …”

Section: Introductionmentioning

confidence: 99%

Efficient One‐Pot Friedel–Crafts Acylation of Benzene and its Derivatives with Unprotected Aminocarboxylic Acids in Polyphosphoric Acid

Ivanov

Nikolova

Statkova-Abeghe

2006

Synthetic Communications

View full text Add to dashboard Cite

Substituted (1,2-Diarylethyl)amide Acyl-CoA:Cholesterol Acyltransferase Inhibitors: Effect of Polar Groups on in Vitro and in Vivo Activity

Cited by 24 publications

References 6 publications

Tamoxifen Is a Potent Inhibitor of Cholesterol Esterification and Prevents the Formation of Foam Cells

Tamoxifen Is a Potent Inhibitor of Cholesterol Esterification and Prevents the Formation of Foam Cells

AM-251 and SR144528 are acyl CoA:cholesterol acyltransferase inhibitors

Efficient One‐Pot Friedel–Crafts Acylation of Benzene and its Derivatives with Unprotected Aminocarboxylic Acids in Polyphosphoric Acid

Contact Info

Product

Resources

About