TMP-153, a novel ACAT inhibitor, inhibits cholesterol absorption and lowers plasma cholesterol in rats and hamsters

Sugiyama, Yasuo; Ishikawa, Eiichiro; Odaka, Hiroyuki; Miki, Nanami; Tawada, Hiroyuki; Ikeda, Hitoshi

doi:10.1016/0021-9150(94)05429-m

Cited by 35 publications

(11 citation statements)

References 19 publications

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“…Although, YM17E had a less potent effect on serum lipid profile in normal rats compared to the dramatic effect in hypercholesterolemic animals, it still significantly lowered non-HDL cholesterol and free fatty acids in these animals (Table 1). These observations were consistent with previous reports on other ACAT inhibi tors that also showed hypocholesterolemic activity in normocholesterolemic animals (19). We have not exam ined the effect of YM 17E on apoB protein production, but there is some evidence that ACAT inhibitor reduces hepatic apoB secretion.…”

Section: Discussionsupporting

confidence: 93%

“…There was little change in the serum triglycer ide level in cholesterol-fed rats by ACAT inhibition, sug gesting that YM 17E has no effect on lipase-induced HDL generation in these animals. A similar result was reported in hamsters (19), but in cholesterol-fed rabbits, inhibition of ACAT decreased plasma TG significantly without affecting HDL cholesterol (23).…”

Section: Discussionsupporting

confidence: 85%

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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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Section: Discussionsupporting

confidence: 93%

Section: Discussionsupporting

confidence: 85%

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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“…Recent studies have shown that the JNK signaling is important for IL-6 expression in response to free cholesterol loading. 26 However, Am80 did not alter JNK1/2 phosphorylation 26 induced by the ACAT inhibitor (TMP-153) treatment 27 in Raw264 cell (unpublished observations, Takeda and Manabe, 2005), suggesting that the JNK pathway is not involved in the inhibition of IL-6 expression by Am80.…”

Section: Discussionmentioning

confidence: 99%

Synthetic Retinoid Am80 Reduces Scavenger Receptor Expression and Atherosclerosis in Mice by Inhibiting IL-6

Takeda

Manabe

Shindo

et al. 2006

ATVB

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Background-Macrophage scavenger receptors facilitate the uptake of modified low-density lipoprotein (LDL), formation of foam cells, and development of atherosclerosis. Given that proinflammatory cytokines, including IL-6, can modulate the macrophage foaming process, the aim of the present study was to determine whether the synthetic retinoic acid receptor-␣/␤-specific agonist Am80, which is also an IL-6 inhibitor, can modulate macrophage lipid accumulation and foam cell formation. Methods and Results-Am80 suppressed IL-6 production induced by 12-myristate 13-acetate (PMA) or angiotensin II in mouse Raw264 macrophages. It also suppressed expression of the 2 major scavenger receptors (scavenger receptor-A [SR-A] and CD36), in part by inhibiting IL-6, and inhibited macrophage foam cell formation. Systemic administration of Am80 led to reductions in the areas of atherosclerotic lesions and foam cell accumulation in the aortas of apolipoprotein E (apoE)-deficient mice and reduced serum concentrations of IL-6 and IL-1␤ without affecting body weights, serum lipid profiles or IL-10 levels. Conclusions-Am80 suppresses scavenger receptor expression and macrophage foam cell formation in vitro and prevents atherogenesis in apoE-deficient mice in vivo. This suggests Am80 is a novel candidate agent that could be highly useful in the prevention and treatment of atherosclerosis.

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“…This reduced total serum cholesterol level was due to a reduction in the non-HDL cholesterol level, as observed for mice and rabbits. It has been reported that some ACAT inhibitors reduce the serum cholesterol level in normolipidemic hamsters [22][23][24], and that this reduction is due to the suppression of VLDL secretion from liver. These reports support our hypothesis that the effect of SMP-500 on the serum cholesterol level may be due to the suppression of VLDL secretion.…”

Section: Discussionmentioning

confidence: 99%

Effect of SMP-500, a Novel Acyl-CoA:Cholesterol Acyltransferase Inhibitor, on the Cholesterol Esterification and Its Hypocholesterolemic Properties

Ioriya¹,

Noguchi²,

Muraoka³

et al. 2002

Pharmacology

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We investigated the effects of SMP-500, a novel acyl-CoA:cholesterol acyltransferase (ACAT) inhibitor, on ACAT activities in the liver and intestine, and in macrophages. We measured its effects on the serum cholesterol levels and hepatic cholesterol content in mice, rabbits and hamsters. SMP-500 inhibited ACAT activities in rabbit liver and small intestine microsomes with IC₅₀ values of 72 and 84 nmol/l, respectively, and acted as a competitive inhibitor of rabbit liver ACAT. SMP-500 potently inhibited cholesterol esterification in rat peritoneal macrophages (IC₅₀ = 15 nmol/l). In high-fat and high-cholesterol diet-fed mice and in high-cholesterol diet-fed rabbits, SMP-500 reduced the serum cholesterol levels and the hepatic cholesterol content. SMP-500 also reduced the serum and hepatic cholesterol in normal chow-fed hamsters in a dose-dependent manner. In all the animal models, SMP-500 reduced the hepatic free cholesterol content as well as the total and esterified cholesterol. Administered orally, SMP-500 had a direct inhibitory effect on hepatic ACAT activity. These results indicate that SMP-500 is a potent and competitive ACAT inhibitor and may have a therapeutic potential for treating hypercholesterolemia and atherosclerosis.

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TMP-153, a novel ACAT inhibitor, inhibits cholesterol absorption and lowers plasma cholesterol in rats and hamsters

Cited by 35 publications

References 19 publications

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

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

Synthetic Retinoid Am80 Reduces Scavenger Receptor Expression and Atherosclerosis in Mice by Inhibiting IL-6

Effect of SMP-500, a Novel Acyl-CoA:Cholesterol Acyltransferase Inhibitor, on the Cholesterol Esterification and Its Hypocholesterolemic Properties

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