Corpus ID: 46682224

RPR 107393, a potent squalene synthase inhibitor and orally effective cholesterol-lowering agent: comparison with inhibitors of HMG-CoA reductase.

@article{Amin1997RPR1A,
  title={RPR 107393, a potent squalene synthase inhibitor and orally effective cholesterol-lowering agent: comparison with inhibitors of HMG-CoA reductase.},
  author={Dilip Amin and Ruth Z. Rutledge and S N Needle and Helen Galczenski and Kent William Neuenschwander and Anthony C. Scotese and Martin P. Maguire and R C Bush and David J. Hele and Glenda E. Bilder and Mark H. Perrone},
  journal={The Journal of pharmacology and experimental therapeutics},
  year={1997},
  volume={281 2},
  pages={
          746-52
        }
}
Squalene synthase catalyzes the reductive dimerization of two molecules of farnesyl pyrophosphate to form squalene and is the first committed step in sterol synthesis. A specific inhibitor of squalene synthase would inhibit cholesterol biosynthesis but not prevent the formation of other products of the isoprenoid pathway, such as dolichol and ubiquinone. RPR 107393 [3-hydroxy-3-[4-(quinolin-6-yl)phenyl]-1-azabicyclo[2-2-2]octane dihydrochloride] and its R and S enantiomers are potent inhibitors… Expand
Effect of ER-27856, a novel squalene synthase inhibitor, on plasma cholesterol in rhesus monkeys: comparison with 3-hydroxy-3-methylglutaryl-coa reductase inhibitors.
TLDR
Results demonstrate that ER-27856 had more potent hypocholesterolemic activity and less hepatotoxic effect than HMGRIs, and may contribute to the treatment of hypercholesterolesmic patients. Expand
Syntheses of 3-ethylidenequinuclidine derivatives as squalene synthase inhibitors. Part 2: enzyme inhibition and effects on plasma lipid levels.
TLDR
3-Ethylidenequinuclidine derivatives incorporating an unsubstituted 9H-carbazole moiety reduced plasma non-HDL cholesterol levels and did not affect plasma transaminase levels, indicating a lack of hepatotoxicity. Expand
Pharmacologic Inhibition of Squalene Synthase and Other Downstream Enzymes of the Cholesterol Synthesis Pathway: A New Therapeutic Approach to Treatment of Hypercholesterolemia
Hypercholesterolemia is a major risk factor for the development of atherosclerotic vascular diseases. The most popular agents for cholesterol reduction are the statin drugs, which are competitiveExpand
Squalene synthase inhibitors suppress triglyceride biosynthesis through the farnesol pathway in rat hepatocytes Published, JLR Papers in Press, October 16, 2002. DOI 10.1194/jlr.M200316-JLR200
TLDR
The results suggest that SQS inhibitors reduce triglyceride biosynthesis by suppressing fatty acid biosynthesis via an increase in intracellular farnesol and its derivatives. Expand
HMG-CoA reductase regulation: use of structurally diverse first half-reaction squalene synthetase inhibitors to characterize the site of mevalonate-derived nonsterol regulator production in cultured IM-9 cells.
TLDR
Observations strongly suggest that nonsterol-mediated post-transcriptional mechanisms regulating HMGR activity remain intact after SQS first half-reaction inhibition, indicating thatNonsterol regulator production is independent of SQS action and ruling out PSQPP, squalene and their metabolites as possible mediators. Expand
Synthesis, Characterization and In vitro Evaluation of N-Substituted- Sulfomoyl-Phenyl-Amino Carboxylic Acid Derivatives as Squalene Synthase Inhibitors
Squalene Synthase is one of the cholesterol biosynthetic pathway enzymes, inhibition of which produces potent lipid lowering action. A variety of chemical classes have been evaluated for itsExpand
Squalene epoxidase as hypocholesterolemic drug target revisited.
TLDR
The literature was evaluated to understand merits and demerits of pursuing squalene epoxidase as a target for hypocholesterolemic drug development, and to evaluate safety concerns with squalenes ep oxidase inhibitors. Expand
Down-regulation of 3-hydroxy-3-methylglutaryl coenzyme A reductase mRNA levels and synthesis in syrian hamster C100 cells by the oxidosqualene cyclase inhibitor [4'-(6-allyl-ethyl-amino-hexyloxy)-2'-fluoro-phenyl]-(4-bromophenyl)-me thanone (Ro 48-8071): comparison to simvastatin.
TLDR
In vivo inhibition of 2,3-oxidosqualene:lanosterol cyclase by Ro 48-8071 results in an indirect down-regulation of 3-hydroxy-3-methylglutaryl CoA reductase (HMGR) activity, which is attributed to increased levels of oxysterols, produced upon partial inhibition of OSC, that suppress HMGR and other sterol-responsive genes. Expand
Lipid-lowering (hetero)aromatic tetrahydro-1,4-oxazine derivatives with antioxidant and squalene synthase inhibitory activity.
TLDR
A number of newly synthesized 2-[4-(hetero)aromatic]phenyl-2-hydroxy-tetrahydro-1,4-oxazine derivatives were found to inhibit lipid peroxidation as well as rat squalene synthase, pointing to useful structural approaches for the design of antiatherosclerotic agents. Expand
Synthesis and biological evaluation of quinuclidine derivatives incorporating phenothiazine moieties as squalene synthase inhibitors.
TLDR
Oral dosing of compound 19 to hamsters demonstrated effective reduction of both plasma total cholesterol levels and plasma triglyceride levels, and enantiomerically pure (-)-19, YM-53546, was found to be more potent than the corresponding (+)-enantiomer. Expand
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References

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Lipophilic 1,1-bisphosphonates are potent squalene synthase inhibitors and orally active cholesterol lowering agents in vivo.
TLDR
It is reported that isoprenyl 1,1-bisphosphonates and related analogs are potent inhibitors of rat microsomal squalene synthase and members of this family are potent inhibitor of cholesterol biosynthesis in rats on intravenous and oral dosing, as well as cholesterol lowering agents in rats and hamsters. Expand
Mevalonic acid-dependent degradation of 3-hydroxy-3-methylglutaryl-coenzyme A reductase in vivo and in vitro.
TLDR
It is concluded that the MVA-derived component that is required for the accelerated degradation of HMG-CoA reductase is derived from farnesyl disphosphate and/or squalene in the isoprenoid biosynthetic pathway. Expand
Identification of farnesol as the non-sterol derivative of mevalonic acid required for the accelerated degradation of 3-hydroxy-3-methylglutaryl-coenzyme A reductase.
TLDR
The present studies demonstrate for the first time that the accelerated degradation of HMG-CoA reductase can be initiated in vitro and propose that this isoprenoid alcohol is important in this process in intact cells. Expand
Bisphosphonates used for the treatment of bone disorders inhibit squalene synthase and cholesterol biosynthesis.
TLDR
Structural modifications on YM 175 to enhance cell permeability may result in a new class of cholesterol-lowering agents. Expand
Non-sterol compounds that regulate cholesterogenesis. Analogues of farnesyl pyrophosphate reduce 3-hydroxy-3-methylglutaryl-coenzyme A reductase levels.
TLDR
Farnesyl acetate and ethyl farnesyl ether stimulate post-transcriptional down-regulation of 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase, the rate-limiting enzyme in the biosynthesis of cholesterol and isoprenoids, and directly disrupt sterol synthesis. Expand
RG 12561 (dalvastatin): a novel synthetic inhibitor of HMG-CoA reductase and cholesterol-lowering agent.
TLDR
In WHHL rabbits and cholestyramine-fed hamsters, RG 12561 and lovastatin reduced serum cholesterol by 17 and 16%, respectively, and these results demonstrate thatRG 12561 is a potent cholesterol-lowering agent. Expand
CS-514, a competitive inhibitor of 3-hydroxy-3-methylglutaryl coenzyme A reductase: tissue-selective inhibition of sterol synthesis and hypolipidemic effect on various animal species.
TLDR
CS-514 markedly reduced serum cholesterol levels in dogs, monkeys and rabbits, including Watanabe heritable hyperlipidemic rabbits, an animal model for familial hypercholesterolemia in man, but did not reduce those in rats and mice. Expand
Discovery, biosynthesis, and mechanism of action of the zaragozic acids: potent inhibitors of squalene synthase.
TLDR
The zaragozic acids are very potent inhibitors of squalene synthase that inhibit cholesterol synthesis and lower plasma cholesterol levels in primates and have potential to be developed either as cholesterol lowering agents and/or as antifungal agents. Expand
Regulation of 3-hydroxy-3-methylglutaryl coenzyme A reductase gene expression by sterols and nonsterols in rat liver.
TLDR
It was found that while dietary cholesterol had little effect on HMG-CoA reductase mRNA levels; immunoreactive protein was reduced to barely detectable levels, as was enzyme activity; any possible effect on catalytic efficiency is thus ruled out. Expand
Squalestatin 1, a potent inhibitor of squalene synthase, which lowers serum cholesterol in vivo.
TLDR
In marmosets, a species with a lipoprotein profile similar to that of man, squalestatin 1 lowers serum cholesterol by up to 75%, which will allow further investigation of the control of the sterol biosynthesis pathway and could also lead to the development of new therapies for elevated serum cholesterol. Expand
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