Atherosclerosis

1994

DOI: 10.1016/0021-9150(94)93678-1

|View full text |Cite

|

Sign up to set email alerts

|

SR-9223i/SK&F 99085, a novel hypocholesterolemic agent with multiple anti-atherosclerotic properties, inhibits ACAT and lipoprotein oxidation

Eric J. Niesor¹,

Pierre Maechler²,

et al.

Help me understand this report

Search citation statements

Order By: Relevance

Paper Sections

Select...

Discussion2

Effect Of 11-bisphosphonate Esters On Plasma Cholesterol1

Citation Types

Supporting

0

Mentioning

3

Contrasting

0

Year Published

1995

1995

2011

2011

Publication Types

Select...

Article4

Relationship

Self Cite0

Independent4

Authors

Journals

Cited by 4 publications

(3 citation statements)

References 0 publications

Supporting

0

Mentioning

3

Contrasting

0

Order By: Relevance

“…SR-9223i prevents this compensatory mechanism by increasing the rate of degradation of HMG CoA reductase, the rate limiting enzyme in the biosynthesis of cholesterol (as discussed above). SR-9223i is also an antioxidant [9] which we have shown to preferentially associate with the VLDL and LDL fractions in the cholesterol-fed New Zealand white rabbits used in these studies. This partitioning into the lower density lipoproteins is of great importance as it is believed to be the oxidation of the lipids in these particles that releases factors that attract monocytes and cause them to differentiate into macrophages, leading to foam cell formation [17,18].…”

Section: Discussionmentioning

confidence: 76%

“…The hypocholesterolaemic effect of SR-9223i is not the only potential anti-atherosclerotic activity of this compound. SR-9223i has been shown to inhibit ACAT, the intracellular enzyme that esterifies cholesterol [9]. This action would be expected to reduce the rate of cholesterol absorption from the gastrointestinal tract [15,16].…”

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

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

Gee²,

et al. 2011

Arzneimittelforschung

View full text Add to dashboard Cite

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.

“…SR-9223i prevents this compensatory mechanism by increasing the rate of degradation of HMG CoA reductase, the rate limiting enzyme in the biosynthesis of cholesterol (as discussed above). SR-9223i is also an antioxidant [9] which we have shown to preferentially associate with the VLDL and LDL fractions in the cholesterol-fed New Zealand white rabbits used in these studies. This partitioning into the lower density lipoproteins is of great importance as it is believed to be the oxidation of the lipids in these particles that releases factors that attract monocytes and cause them to differentiate into macrophages, leading to foam cell formation [17,18].…”

Section: Discussionmentioning

confidence: 76%

“…The hypocholesterolaemic effect of SR-9223i is not the only potential anti-atherosclerotic activity of this compound. SR-9223i has been shown to inhibit ACAT, the intracellular enzyme that esterifies cholesterol [9]. This action would be expected to reduce the rate of cholesterol absorption from the gastrointestinal tract [15,16].…”

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)

Gee²,

et al. 2011

Arzneimittelforschung

View full text Add to dashboard Cite

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.

“…The 1,1-bisphosphonate esters decrease plasma cholesterol in a number of animal species [103][104][105] without the species specificity which characterises the standard hypocholesterolemic drugs (fibrates and statins).…”

Section: Effect Of 11-bisphosphonate Esters On Plasma Cholesterolmentioning

confidence: 99%

The Nuclear Receptors FXR and LX alpha Potential Targets for the Development of Drugs Affecting Lipid Metabolism and Neoplastic Diseases

et al. 2001

View full text Add to dashboard Cite

The orphan nuclear receptors FXR and LXRalpha have become challenging targets for the discovery of new therapeutic agents. Bile acids and hydroxysterol intermediates are the respective natural ligands of these two structurally and functionally closely related receptors. Both FXR and LXRalpha; are thought to play a major role in the control of cholesterol catabolism by regulating the expression of cholesterol 7alpha-hydroxylase, the rate limiting enzyme of bile acid synthesis. Reverse cholesterol transport might also be affected by FXR and LXR since they control the expression of PLTP and CETP, two proteins involved in the transfer of phospholipid, cholesterol and cholesteryl esters among plasma lipoproteins. A new class of potent synthetic activators of FXR, the 1,1-bisphosphonate esters, has been discovered which up regulate the Intestinal Bile Acid Binding Protein gene (I-BABP) as demonstrated for chenodeoxycholic acid, however there are no known synthetic activators yet identified for LXRalpha. The evaluation of FXR as a potential target for the development of drugs affecting plasma cholesterol can take advantage of the fact that the activators of FXR (farnesol, bile acids and the 1,1-bisphosphonate esters) have been studied in various in vitro and in vivo models. Administration of chenodeoxycholic acid to animals and man did not result in the increase in plasma cholesterol expected from a decrease in cholesterol 7alpha-hydroxylase expression. Like farnesol, the 1,1-bisphosphonate esters increase the rate of degradation of HMGCoA reductase and have the unexpected property of inducing hypocholesterolemia in normal animals. The natural and synthetic FXR agonists trigger differentiation, inhibit cell proliferation and are potent inducers of apoptosis. The 1,1-bisphosphonate ester SR-45023A (Apomine) is presently being developed as an antineoplastic drug.

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

¹

,

²

,

³

et al. 1996

Journal of Biological Chemistry

View full text Add to dashboard Cite

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.

scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.

Contact Info

hi@scite.ai

10624 S. Eastern Ave., Ste. A-614

Henderson, NV 89052, USA

Product

Browser Extension Assistant by scite Citation Statement Search Reference Check Visualizations Dashboards Explore Journals Explore Organizations Explore Funders Embedding Badge Embedding Citation Search Pricing

Resources

Blog Help & FAQ Accessibility Statement API Terms For Universities & Governments For Researchers For Publishers For Corporate, Pharma & Enterprise Author Marketing Become an Affiliate Get an organization trial or quote scite Data & Services

About

News & Press Careers Read our Paper Coverage

Blog Terms and Conditions API Terms Privacy Policy Contact Cookie Preferences Do Not Sell or Share My Personal Information

Copyright © 2024 scite LLC. All rights reserved.

Made with 💙 for researchers

Part of the Research Solutions Family.