Review: Cardiovascular &amp; Renal Recent developments in hypocholesterolaemic agents

Lee, Helen T.; Picard, J. A.

doi:10.1517/13543776.5.5.397

Cited by 7 publications

(5 citation statements)

References 73 publications

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“…However, these compounds did not exhibit hypocholesterolemic activity. Conversion of benzyl residue of 19 into an n-heptyl (26), n-octyl (27), n-nonyl (28), or n-decyl (29) residue but not an n-hexyl (25) residue significantly increased ACAT inhibitory activity.…”

Section: Resultsmentioning

confidence: 98%

“…For these derivatives, unlike those with a 2,4-dimethyl residue in the C-phenyl ring (25)(26)(27)(28)(29), the drug efficacy did not increase according to the length of the nalkyl chain at R 2 in the A-phenyl ring, and the n-octyl derivative (45) had the highest level of hypocholesterolemic activity.…”

Section: Resultsmentioning

confidence: 99%

“…Clinical development of ACAT inhibitors, however, has not been successful, 25,26) be- [27][28][29][30][31][32][33][34][35][36][37][38] Recently, ACAT has been classified into two isozymes, ACAT-1 and ACAT-2, and research suggests that they differ in terms of their distribution in the body. [39][40][41][42][43] Two reasons are believed to be involved in why the numerous ACAT inhibitors that have been developed thus far have not been clinically successful.…”

Section: Resultsmentioning

confidence: 99%

“…With modification of region A in the molecule (Fig. 1), phenylpiperamides (19)(20)(21)(22)(23)(24)(25)(26)(27)(28)(29)(42)(43)(44)(45)(46) were prepared by amidation of 8 with corresponding phenylpiperazine, followed by alkylation with appropriate halide.…”

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Structure-Activity Relationships of N-(3,5-Dimethoxy-4-n-octyloxycinnamoyl)-N'-(3,4-dimethylphenyl)piperazine and Analogues as Inhibitors of Acyl-CoA: Cholesterol O-Acyltransferase.

Ohishi

Aiyama

Hatano

et al. 2001

CHEMICAL & PHARMACEUTICAL BULLETIN

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Since the pioneering results of the Framingham study disclosed in 1971, 1) hypercholesterolemia has been recognized as a major risk factor for the development of coronary heart disease (CHD).2,3) Agents controlling total plasma cholesterol levels are expected to serve as an effective therapeutic method for atherosclerosis, 4) since lowering plasma cholesterol levels has been proven to reduce mortality from myocardial infarction.5) Acyl-CoA: cholesterol O-acyltransferase (ACAT, EC 2.3.1.26) 6,7) is an intracellular enzyme responsible for catalyzing the esterification of free cholesterol with fatty acyl-CoA to produce cholesteryl esters. This enzyme plays important roles in the absorption of dietary cholesterol from the small intestine, the secretion of very lowdensity lipoprotein (VLDL) from the liver, and the accumulation of cholesteryl esters in atherosclerotic lesions. Inhibition of ACAT should reduce the absorption of cholesterol, lower plasma cholesterol levels, [8][9][10][11][12] and should arrest the progression and promote the regression of atherosclerotic plaque. 13,14) Therefore, ACAT inhibitors are a prime objective in the development of new therapeutic agents for hypercholesterolemia and atherosclerosis. 15) On this basis, metabolites were screened from about three thousand fungi and numerous plant components that produce an ACAT inhibitor. Of these, it was found that 1-(4-hydroxy-3-methoxyphenyl)-7-phenylhept-1-en-3-one (1, Yakuchinone B), which is a component of the seeds of Alpinia oxyphylla MIQUEL (Zingiberaceae), 16) has ACAT inhibitory activity. In order to obtain ACAT inhibitors that exhibit a high level of hypocholesterolemic activity in vivo, the structure-activity relationships of three structural moieties of Yakuchinone B (1) as the lead compound ( Fig. 1) were examined. The compounds prepared were tested for the ability to inhibit the microsomal ACAT from rat liver and to suppress the elevation of plasma cholesterol levels in rats given a high cholesterol diet.The present paper will describe the structure-activity relationships and biological activities of these novel ACAT inhibitors.Chemistry Diarylheptanoids (1-7) were synthesized by condensation of 1-phenyl-5-hexanone with corresponding benzaldehydes according to the previously described method. 17)As shown in Chart 1, phenylalkylamides (11, 13-15) or anilides (12, 17, 18) were prepared by alkylation of 8, followed by amidation with appropriate phenylalkylamine or aniline by 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDC) in CHCl 3 .Phenylpiperamides (16, 19-46) can be synthesized from 8 via intermediates 9a, b or 10a, b (Chart 1). In the case of the modification of region C in the molecule (Fig. 1), phenylpiperamides (16, 30-41) were prepared by alkylation of 8 with corresponding halide, followed by amidation with appropriate phenylpiperazine. With modification of region A in the molecule (Fig. 1), phenylpiperamides (19-29, 42-46) were prepared by amidation of 8 with corresponding phenylpiperazine, followed by alkyla...

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Section: Resultsmentioning

confidence: 98%

Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

mentioning

confidence: 99%

See 2 more Smart Citations

Structure-Activity Relationships of N-(3,5-Dimethoxy-4-n-octyloxycinnamoyl)-N'-(3,4-dimethylphenyl)piperazine and Analogues as Inhibitors of Acyl-CoA: Cholesterol O-Acyltransferase.

Ohishi

Aiyama

Hatano

et al. 2001

CHEMICAL & PHARMACEUTICAL BULLETIN

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“…Compounds 1 and 2 possess dual activity consisting of inhibition of cholesterol O -acyltransferase (ACAT) and up-regulation of LDL-R. Although inhibition of ACAT is believed to reduce the absorption of dietary cholesterol in the small intestine, , thereby lowering serum lipid level, and to prevent the progression of atherosclerotic lesions, numerous clinical trial studies of potent ACAT inhibitors have shown poor efficacy, with no ACAT inhibitor in clinical use so far . Safety concerns have also been reported with some ACAT inhibitors …”

Section: Introductionmentioning

confidence: 99%

A Novel Class of Antihyperlipidemic Agents with Low Density Lipoprotein Receptor Up-Regulation via the Adaptor Protein Autosomal Recessive Hypercholesterolemia

et al. 2010

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We have previously reported compound 2 as a inhibitor of acyl-coenzyme A:cholesterol O-acyltransferase (ACAT) and up-regulator of the low density lipoprotein receptor (LDL-R) expression. In this study we focused on compound 2, a unique LDL-R up-regulator, and describe the discovery of a novel class of up-regulators of LDL-R. Replacement the methylene urea linker in compound 2 with an acylsulfonamide linker kept a potent LDL-R up-regulatory activity, and subsequent optimization work gave compound 39 as a highly potent LDL-R up-regulator (39; EC(25) = 0.047 microM). Compound 39 showed no ACAT inhibitory activity even at 1 microM. The sodium salts of compound 39 reduced plasma total and LDL cholesterol levels in a dose-dependent manner in an experimental animal model of hyperlipidemia. Moreover, we revealed in this study using RNA interference that autosomal recessive hypercholesterolemia (ARH), an adaptor protein of LDL-R, is essential for compound 39 up-regulation of LDL-R expression.

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Powder extrusion: Fundamentals and different applications

Wolfson

Никольский

1997

Polymer Engineering & Sci

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We propose a novel polymer extrusion process, known as the solid state shear extrusion pulverization and modification (SSSE process), based on the simultaneous action of shear deformation and pressure at selected temperatures. This process can be used for continuous pulverization and copulverization of various polymers. Including different blends, filled materials, thermoplastics, vulcanized rubbers, crosslinked polymers, polymer composites, and natural polymers. Various aspects of this process are considered, including unusual microstructure and properties of powders, low energy consumption, and mechanochemical effects. Possible applications of SSSE to polymer/rubber recycling and to obtaining advanced polymer powders and modified powders are considered, together with scaling‐up problems of equipment suitable for industrial application.

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Review: Cardiovascular & Renal Recent developments in hypocholesterolaemic agents

Cited by 7 publications

References 73 publications

Structure-Activity Relationships of N-(3,5-Dimethoxy-4-n-octyloxycinnamoyl)-N'-(3,4-dimethylphenyl)piperazine and Analogues as Inhibitors of Acyl-CoA: Cholesterol O-Acyltransferase.

Structure-Activity Relationships of N-(3,5-Dimethoxy-4-n-octyloxycinnamoyl)-N'-(3,4-dimethylphenyl)piperazine and Analogues as Inhibitors of Acyl-CoA: Cholesterol O-Acyltransferase.

A Novel Class of Antihyperlipidemic Agents with Low Density Lipoprotein Receptor Up-Regulation via the Adaptor Protein Autosomal Recessive Hypercholesterolemia

Powder extrusion: Fundamentals and different applications

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