Toxicologic Effects of a Novel Acyl-CoA: Cholesterol Acyltransferase Inhibitor in Cynomolgus Monkeys

Reindel, J. F.; Dominick, Mark A.; Bocan, T. M. A.; Gough, A. W.; McGuire, Edward J.

doi:10.1177/019262339402200505

Cited by 39 publications

(30 citation statements)

References 37 publications

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“…The structure-activity relationship studies of the derivatives with substituents in the C-phenyl ring, which had an ndecyl residue at R 2 in the A-phenyl ring (29)(30)(31)(32)(33)(34)(35)(36)(37)(38)(39)(40)(41)(42), indicate the following. Results for monomethyl-substituted compounds (31)(32)(33) demonstrated that a 4-methyl residue was very important in exhibiting a high level of hypocholesterolemic activity in vivo, while a 2-methyl or 3-methyl residue was not.…”

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%

“…In the case of the modification of region C in the molecule (Fig. 1), phenylpiperamides (16,(30)(31)(32)(33)(34)(35)(36)(37)(38)(39)(40)(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.…”

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confidence: 99%

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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: 99%

Section: Resultsmentioning

confidence: 99%

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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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“…Both these effects suggest the generally known risk of secretory diarrhea caused by malabsorp tion of dietary lipids and excess bile acids. Dominick et al (24,25) recently reported diarrhea! episodes in ACAT inhibitor-treated beagle dogs, but did not refer to this in detail.…”

Section: Discussionmentioning

confidence: 99%

Pharmacological Properties of YM17E, an Acyl-CoA:Cholesterol Acyltransferase Inhibitor, and Diarrheal Effect in Beagle Dogs.

Kashiwa¹,

Masuyama²,

Miyauchi³

et al. 1997

Jpn.J.Pharmacol

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YM17E (1,3-bis[[1-cycloheptyl-3-(p-dimethylaminophenyl)ureido]methyl]benzene dihydro chloride) was found to be a potent inhibitor of acyl-CoA:cholesterol acyltransferase (ACAT) in rabbit liver and intestine microsomes. Dixon plot analysis revealed that YM17E inhibited microsomal ACAT in a non-competitive manner. YM17E induced a marked decrease in serum cholesterol, especially in non-high density lipoprotein (HDL) fractions, in cholesterol-fed rats and rats fed normal chow. Measurement of bile secretion after oral administration of YM17E in cholesterol-fed rats showed that the drug markedly accelerated the secretion of bile acids and neutral sterols. Furthermore, absorption of [3H]cholesterol from the gut of cholesterol-fed rats was significantly inhibited by YM17E. From these results, the hypocholes terolemic activity of YM17E in these animals resulted from both a decrease in cholesterol absorption from the gut and the stimulation of excretion of cholesterol from the liver into bile. However, YM17E caused secre tory diarrhea in beagle dogs at near lipid lowering doses. When YM17E was administered at the same total dosage but divided into 5 daily administrations, the incidence of diarrhea was significantly reduced while its cholesterol lowering effect became stronger. These results suggest that the inhibition of intestinal and/or liver ACAT increases the risk of diarrhea development which, however, can be avoided by controlled drug administration in beagle dogs.

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“…A number of acyl coenzyme A:cholesterol acyltransferase inhibitors have been synthesized, and their pharmacological profiles were evaluated in animals and humans. However, several adverse effects such as adrenal toxicity (Vernetti et al, 1993;Reindel et al, 1994;Matsuo et al, 1996), diarrhea (Kashiwa et al, 1997), and hepatotoxicity (Ishi et al, 1994;Nakaya et al, 1994) and various elusive efficacies in humans (Harris et al, 1990;Hainer et al, 1994;Tardif et al, 2004) have been revealed, and none of these compounds has so far succeeded in clinical development. Pactimibe sulfate was selected as a clinical development candidate showing good oral absorbability and potent pharmacological effects in apolipoprotein Edeficient mice (Terasaka et al, 2007) and Watanabe heritable hyperlipidemic rabbits (Kitayama et al, 2006b) without showing significant adrenal toxicity even in dogs, the most sensitive animal species.…”

Section: Introductionmentioning

confidence: 99%

Effects of Ketoconazole and Quinidine on Pharmacokinetics of Pactimibe and Its Plasma Metabolite, R-125528, in Humans

Kotsuma

Tokui²,

Freudenthaler³

et al. 2008

Drug Metab Dispos

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ABSTRACT:Pactimibe sulfate is a novel acyl coenzyme A:cholesterol acyltransferase inhibitor developed for the treatment of hypercholesterolemia and atherosclerotic diseases. Pactimibe has two equally dominant clearance pathways forming R-125528 by CYP3A4 and M-1 by CYP2D6 in vitro. R-125528 is a plasma metabolite and is cleared solely by CYP2D6 despite its acidity. To evaluate contributions of the cytochrome P450 enzymes on the pharmacokinetics of pactimibe and R-125528 in humans, drug-drug interaction studies using ketoconazole and quinidine were conducted. Eighteen healthy male subjects were given a single dose of pactimibe sulfate without and with 400 mg of ketoconazole (q.d.). With the concomitant treatment, the area under the plasma concentrationtime curve (AUC 0-inf ) of pactimibe modestly increased 1.7-fold and AUC 0-tz of R-125528 decreased by 55%. In addition, 17 healthy male subjects were given a single dose of pactimibe sulfate without and with 600 mg of quinidine (b.i.d.). With the concomitant treatment, the AUC 0-inf for pactimibe modestly increased 1.7-fold. On the other hand, the AUC 0-tz of R-125528 was markedly elevated 5.0-fold, although the AUC 0-inf could not be adequately defined because the terminal elimination phase of R-125528 was not obtained in the study period up to 72 h. As the f m CYP3A4 and f m CYP2D6 values of pactimibe estimated from in vitro studies were 0.40 and 0.33, respectively, AUC increase ratios of pactimibe were estimated to be 1.7 with ketoconazole and 1.5 with quinidine. These values were well in accordance with the values observed in this study. Moreover, the f m CYP2D6 of R-125528 estimated to be almost 1 would well explain the accumulation of R-125528 observed with the quinidine treatment.Pactimibe sulfate [7-(2, 2-dimethylpropanamido)-4,6-dimethyl-1-octylindolin-5-yl] acetic acid hemisulfate (formerly named CS-505) (Fig. 1A) is a novel lipophilic acyl coenzyme A:cholesterol acyltransferase inhibitor developed for the treatment of hypercholesterolemia and atherosclerotic diseases (Kitayama et al., 2006a,b,c;Nissen et al., 2006). A number of acyl coenzyme A:cholesterol acyltransferase inhibitors have been synthesized, and their pharmacological profiles were evaluated in animals and humans. However, several adverse effects such as adrenal toxicity (Vernetti et al., 1993;Reindel et al., 1994;Matsuo et al., 1996), diarrhea (Kashiwa et al., 1997), and hepatotoxicity (Ishi et al., 1994;Nakaya et al., 1994) and various elusive efficacies in humans (Harris et al., 1990;Hainer et al., 1994;Tardif et al., 2004) have been revealed, and none of these compounds has so far succeeded in clinical development. Pactimibe sulfate was selected as a clinical development candidate showing good oral absorbability and potent pharmacological effects in apolipoprotein Edeficient mice (Terasaka et al., 2007) and Watanabe heritable hyperlipidemic rabbits (Kitayama et al., 2006b) without showing significant adrenal toxicity even in dogs, the most sensitive animal species.In vivo biotransformatio...

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Toxicologic Effects of a Novel Acyl-CoA: Cholesterol Acyltransferase Inhibitor in Cynomolgus Monkeys

Abstract: Company. 2800

Cited by 39 publications

References 37 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.

Pharmacological Properties of YM17E, an Acyl-CoA:Cholesterol Acyltransferase Inhibitor, and Diarrheal Effect in Beagle Dogs.

Effects of Ketoconazole and Quinidine on Pharmacokinetics of Pactimibe and Its Plasma Metabolite, R-125528, in Humans

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