Potent Inhibitors of Acyl-CoA:Cholesterol Acyltransferase. 2. Structure−Activity Relationships of NovelN-(2,2-Dimethyl-2,3-dihydrobenzofuran-7-yl)amides

Abstract

Novel N-(2,2-dimethyl-2,3-dihydrobenzofuran-7-yl)amide derivatives 1 were synthesized and tested for their ability to inhibit rabbit small intestinal ACAT (acyl-CoA:cholesterol acyltransferase) and lower serum total cholesterol in cholesterol-fed rats. Among the synthesized compounds, N-(2,2,4,6-tetramethyl-2,3-dihydrobenzofuran-7-yl)amide derivatives showed potent ACAT inhibitory activity. The synthesis and structure-activity relationships of these compounds are described. A methyl group at position 6 of the 2,3-dihydrobenzofuran moiety was important for potent ACAT inhibitory activity. In the series of N-(2,2,4,6-tetramethyl-2,3-dihydrobenzofuran-7-yl) amides, lipophilicity of the acyl moiety was necessary for the potent ACAT inhibitory activity. The highly lipophilic acid amides N-(2,2,4,6-tetramethyl-2,3-dihydrobenzofuran-7-yl)-2,2- dimethyldodecanamide (10) and 6-(4-chlorophenoxy)-N-(2,2,4,6-tetramethyl-2,3-dihydrobenzofuran-7-y l)-2,2-dimethyloctanamide (50) showed potent activity. Introduction of a dimethylamino group at position 5 of the 2,3-dihydrobenzofuran moiety resulted in highly potent activity. The most potent compound, N-[5-(dimethylamino)-2,2,4,6-tetramethyl-2,3-dihydrobenzofuran-7-yl ]-2,2-dimethyldodecanamide (13, TEI-6620), showed highly potent ACAT inhibitory activity (rabbit small intestine IC50 = 0.020 microM, rabbit liver IC50 = 0.009 microM), foam cell formation inhibitory activity (rat peritoneal macrophage IC50 = 0.030 microM), extremely potent serum cholesterol-lowering activity in cholesterol-fed rats (71% at a dose of 0.3 mg/kg/day po), and good bioavailability in fed dogs (Cmax = 2.68 microg/mL at 1 h, 10 mg/kg po).

Domino Synthesis of 2,3-Dialkylidenetetrahydrofurans via Tandem Prins Cyclization–Skeletal Reorganization

“…In the course of investigating the metathesis of conjugated diynes and aldehydes, it was found that 2,3-dialkylidenetetrahydrofurans were formed in the reaction between 3,5-diynols and aldehydes (Scheme ). Although a flash vacuum pyrolysis of 3-acyloxymethyl-2-methylfuran, an olefination of 2-alkylidenebutyrolactone, and a cyclocondensation of 2-cinnamoyl ketene dithioacetals with oxalyl chloride have been known as preparations of 2,3-dialkylidenetetrahydrofurans that have a further functionalizable diene moiety and are expected to be converted into various biologically interesting polycyclic furans, these methods have limitations in reactants . Herein, we report the domino synthesis of 2,3-dialkylidenetetrahydrofurans via skeletal reorganization of the Prins-cyclized intermediates derived from 3,5-diynols and aldehydes.…”

Unusual sterolic mixture, and 24‐isopropylcholesterol, from the sponge Ciocalypta sp. reduce cholesterol uptake and basolateral secretion in Caco‐2 cells

“…The cholesterol that enters the enterocyte is transferred to endoplasmic reticulum, where it can be esterified by ACAT-2. The role of ACAT-2 in intestinal cholesterol absorption has been demonstrated in many in vitro and in vivo studies [Clark and Tercyak, 1984;Kataoka et al, 1996;Miyazaki et al, 2005].…”

“…Cholesterol esterification involves the covalent attachment of fatty acids to 3-position hydroxyl group of cholesterol to form cholesteryl esters. Employing a number of specific ACAT-2 inhibitors, several studies have shown a reduction in intestinal cholesterol absorption [Clark and Tercyak, 1984;Kataoka et al, 1996;Miyazaki et al, 2005]. Furthermore, ACAT-2 knock out mice are resistant to dietinduced hypercholesterolemia due to defective cholesterol esterification by intestinal cells [Buhman et al, 2000].…”

Comparison and evaluation of the thermooxidative stability of medical natural rubber latex products prepared with a sulfur vulcanization system and a peroxide vulcanization system

“…The cholesterol that enters the enterocyte is transferred to endoplasmic reticulum, where it can be esterified by ACAT‐2. The role of ACAT‐2 in intestinal cholesterol absorption has been demonstrated in many in vitro and in vivo studies [Clark and Tercyak, 1984; Kataoka et al, 1996; Miyazaki et al, 2005].…”

“…Cholesterol esterification involves the covalent attachment of fatty acids to 3‐position hydroxyl group of cholesterol to form cholesteryl esters. Employing a number of specific ACAT‐2 inhibitors, several studies have shown a reduction in intestinal cholesterol absorption [Clark and Tercyak, 1984; Kataoka et al, 1996; Miyazaki et al, 2005]. Furthermore, ACAT‐2 knock out mice are resistant to diet‐induced hypercholesterolemia due to defective cholesterol esterification by intestinal cells [Buhman et al, 2000].…”