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.

Abstract

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...

Inhibitory Effects of N-(3,5-Dimethoxy-4-n-octyloxycinnamoyl)-N'-(3,4-dimethylphenyl)piperazine (YIC-C8-434), an Acyl-CoA: Cholesterol O-Acyltransferase Inhibitor, on Cholesterol Esterification in the Intestine and Liver

“…Previously, we reported that plasma total cholesterol levels in rats fed a high cholesterol diet decreased by 50% when YIC-C8-434 was administered at dose of 2.4 mg/kg/d for 7 d. 8) In the present study, it was clarified that oral administration of YIC-C8-434 directly inhibited both intestinal and hepatic ACAT. It is thus speculated that YIC-C8-434 lowers the total plasma cholesterol level by inhibiting intestinal cholesterol absorption and/or hepatic VLDL cholesterol secretion.…”

“…8) In the present study, we investigated the effect of YIC-C8-434 on the formation of cholesteryl esters, triacylglycerols, and phospholipids in Caco2 and HepG2 cell model systems. As shown in Figs.…”

“…6,7) Fig. 1) 8) is an ACAT inhibitor newly synthesized from Yakuchinone B, 9) which is a component of the seeds of Alpinia oxyphylla MIQUEL (Zingiberaceae). In the previous paper, it was reported that YIC-C8-434 potently inhibits a microsomal ACAT prepared from the liver of rats, HepG2 (a cell line derived from human hepatocarcinoma), and Caco2 (a cell line derived from human colon adenocarcinoma).…”

“…In addition, it exhibits hypocholesterolemic activity when it administered as a dietary admixture to rats fed a high cholesterol diet. 8) The present study was conducted to investigate the inhibitory effect of YIC-C8-434 on cholesterol esterification in the intestinal epithelium and hepatocytes. Furthermore, the effects of the oral administration of YIC-C8-434 on cholesterol absorption from the small intestine and the secretion of VLDL cholesterol from the liver were examined in SpragueDawley rats in vivo.…”

Suppression of Inducible Nitric Oxide Synthase Expression by Yakuchinones and Their Analogues

“…14,15) Yakuchinone B and the structural analogues have been extensively studied as inhibitors of acyl-CoA: cholesterol O-acyltransferase that can be therapeutic agents for hypercholesterolemia and atherosclerosis. 16) Yakuchinone B has also been reported to show inhibitory activity of tyrosinase. The a,b-unsaturated carbonyl conjugated moiety and aromatic ring of yakuchinone B play important roles in the competitive inhibition of tyrosinase.…”