SK&amp;F 99085/SR-9223i, a novel hypocholesterolemic agent with multiple anti-atherosclerotic properties, suppresses HMG-CoA reductase and induces LDL receptor activity by a novel mechanism

Berkhout, Theo; Simon, H.; Niesor, Eric J.; Bentzen, C.; Suckling, Keith E.

doi:10.1016/0021-9150(94)93677-3

Cited by 4 publications

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“…SR-9223i and a compound of similar structure, SR-12813, have been shown to produce a rapid increase in the rate of degradation of this enzyme, thereby reducing the rate of cholesterol synthesis and increasing LDL receptor activity in the liver. The result is an hypocholesterolaemia in normocholesterolaemic animals [8,14]. The hypocholesterolaemic effect of SR-9223i is not the only potential anti-atherosclerotic activity of this compound.…”

Section: Discussionmentioning

confidence: 99%

Hypocholesterolaemic and Antiatherosclerotic Effects of Tetra-iso-propyl 2-(3,5-Di-tert-butyl-4-hydroxyphenyl)ethyl-1, 1-diphosphonate (SR-9223i)

Jackson¹,

Gee²,

Guyon-Gellin³

et al. 2011

Arzneimittelforschung

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Tetra-iso-propyl 2-(3,5-di-tert-butyl-4-hydroxyphenyl)ethyl-1,1-diphosphonate (CAS 126411-13-0, SR-9223i) is a member of a new class of compounds with multiple antiatherosclerotic activities. This report not only describes the cholesterol-lowering properties in four species of animals fed normocholesterolaemic diets but also reductions in lipid deposition in the arteries of cholesterol-fed New Zealand white rabbits following the administration of SR-9223i. Plasma cholesterol concentrations were reduced in mice by 27% (200 mg/kg/day administered in the diet for 10 days), in hamsters by 33% (200 mg/kg/day administered in the diet for 8 days), in dogs by 16% (25 mg/kg/day p.o. for 28 days) and 23% (75 mg/kg/day p.o. for 28 days) and in monkeys by 22% (25 mg/kg/day p.o. for 28 days). Further, the deposition of cholesterol, especially in the esterified form, in the aortae of cholesterol-fed New Zealand white rabbits was inhibited by SR-9223i (50 and 100 mg/kg/day p.o.). At the higher dose, the cholesteryl ester content of the aorta was half that of control animals. SR-9223i, at both doses, also inhibited the accumulation of cholesterol in the liver. SR-9223i has been shown to suppress HMG CoA reductase activity, inhibit ACAT activity and prevent lipid oxidation. These activities, demonstrated in vitro, have now been shown to translate into lipid lowering and antiatherosclerotic activities in vivo.

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Section: Discussionmentioning

confidence: 99%

Hypocholesterolaemic and Antiatherosclerotic Effects of Tetra-iso-propyl 2-(3,5-Di-tert-butyl-4-hydroxyphenyl)ethyl-1, 1-diphosphonate (SR-9223i)

Jackson¹,

Gee²,

Guyon-Gellin³

et al. 2011

Arzneimittelforschung

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SR-12813 lowers plasma cholesterol in beagle dogs by decreasing cholesterol biosynthesis

et al. 1997

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The Novel Cholesterol-lowering Drug SR-12813 Inhibits Cholesterol Synthesis via an Increased Degradation of 3-Hydroxy-3-methylglutaryl-coenzyme A Reductase

Berkhout

Simon

Patel

et al. 1996

Journal of Biological Chemistry

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SR-12813 (tetra-ethyl 2-(3,5-di-tert-butyl-4-hydroxyphenyl)ethenyl-1, 1-bisphosphonate) lowers plasma cholesterol in five species. In this paper we investigate the underlying mechanism using Hep G2 cells. SR-12813 inhibited incorporation of tritiated water into cholesterol with an IC50 of 1.2 microM but had no effect on fatty acid synthesis. Furthermore, SR-12813 reduced cellular 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase activity with an IC50 of 0.85 microM. The inhibition of HMG-CoA reductase activity was rapid with a T1/2 of 10 min. After a 16-h incubation with SR-12813, mRNA levels of HMG-CoA reductase and low density lipoprotein (LDL) receptor were increased. The increased expression of LDL receptor translated into a higher LDL uptake, which can explain the primary hypocholesterolemic effect of SR-12813 in vivo. Western blot analysis indicated that the amount of HMG-CoA reductase protein rapidly decreased in the presence of SR-12813. Pulse-chase experiments with [35S]methionine showed that the T1/2 of HMG-CoA reductase degradation decreased in the presence of SR-12813 from 90 to 20 min. Pre-incubation with 50 microM of lovastatin did not prevent the effects of SR-12813 on HMG-CoA reductase degradation, indicating that the compound does not need mevalonate-derived regulators for its action. It is concluded that SR-12813 inhibits cholesterol synthesis mainly by an enhanced degradation of HMG-CoA reductase.

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SK&F 99085/SR-9223i, a novel hypocholesterolemic agent with multiple anti-atherosclerotic properties, suppresses HMG-CoA reductase and induces LDL receptor activity by a novel mechanism

Cited by 4 publications

References 0 publications

Hypocholesterolaemic and Antiatherosclerotic Effects of Tetra-iso-propyl 2-(3,5-Di-tert-butyl-4-hydroxyphenyl)ethyl-1, 1-diphosphonate (SR-9223i)

Hypocholesterolaemic and Antiatherosclerotic Effects of Tetra-iso-propyl 2-(3,5-Di-tert-butyl-4-hydroxyphenyl)ethyl-1, 1-diphosphonate (SR-9223i)

SR-12813 lowers plasma cholesterol in beagle dogs by decreasing cholesterol biosynthesis

The Novel Cholesterol-lowering Drug SR-12813 Inhibits Cholesterol Synthesis via an Increased Degradation of 3-Hydroxy-3-methylglutaryl-coenzyme A Reductase

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