RPR107393
RPR107393 is an orally active potent selective squalene synthase (SQS) inhibitor. RPR107393 inhibits rat liver microsomal squalene synthase with an IC50 value of 0.8 nM. RPR107393 reduces triglyceride biosynthesis by suppressing fatty acid biosynthesis via an increase in intracellular farnesol and its derivatives. RPR107393 reduces plasma cholesterol in rats and marmosets. RPR107393 can be used for metabolic disease research, such as hypercholesterolemia, hypertriglyceridemia and atherosclerosis.
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- CAS No.: 190841-57-7
- Formule: C22H24Cl2N2O
- Masse moléculaire:403.34
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Stockage:
Please store the product under the recommended conditions in the Certificate of Analysis.
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Activité biologique
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Chemical Information
- Pureté et documentation
- Références
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Help & FAQs
Activité biologique
Description
IC50 & Target
IC50: 0.8±0.2 nM (rat liver microsomal squalene synthase)[1]
In Vitro
RPR107393 (10 min) is a potent inhibitor of rat liver microsomal squalene synthase, with IC50 values of 0.6 to 0.9 nM, and is inactive (3% inhibition at 1 mM) against HMG-CoA reductase from rat liver microsomes[1].
RPR107393 (6 h) concentration-dependently inhibits cholesterol biosynthesis (IC50 = 880 nM) and triglyceride biosynthesis (IC50 = 410 nM) in rat hepatocytes[2].
RPR107393 (10 μM, 2-24 h) decreases the incorporation of [1-14C]acetic acid into lipids in rat hepatocytes in a time-dependent manner, with maximal inhibition of cholesterol and triglyceride biosynthesis occurring at 2 h and 24 h, respectively[2].
RPR107393 (1 μM, 4 h) inhibits cholesterol and triglyceride biosynthesis by 82.4% and 70.0% in rat hepatocytes, respectively, with the latter effect potentiated by MVL supplementation, suggesting a mechanism involving increased FPP derivatives[2].
RPR107393 (1-10 μM, 4 h) increases carnitine-dependent mitochondrial β-oxidation (by 26.5% at 1 μM and 39.5% at 10 μM), it reduces overall triglyceride biosynthesis through a β-oxidation-independent pathway[2].
RPR107393 (10 μM, 4 h) suppresses triglyceride biosynthesis in rat hepatocytes, reducing fatty acid and triglyceride synthesis by 67.7% and 68.5%, respectively, through inhibiting fatty acid synthesis rather than later metabolic stages[2].
MedChemExpress (MCE) has not independently confirmed the accuracy of these methods. They are for reference only.
In Vivo
RPR107393 (20 mg/kg, p.o., b.i.d. or q.d. for 7 days) selectively lowers LDL cholesterol while maintaining a favorable HDL profile in marmosets[1].
MedChemExpress (MCE) has not independently confirmed the accuracy of these methods. They are for reference only.
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Animal Model:Sprague-Dawley rats (130-150 g)[1]
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Dosage:10 and 25 mg/kg
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Administration:p.o., sigle dose
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Result:Reduced cholesterol biosynthesis by 92% at 10 mg/kg, with an approximate ED50 value of 5 mg/kg.
Reduced cholesterol biosynthesis by 74 % after 6 h, and the time for 50% inhibition was ~7 hr at 10 mg/kg.
Inhibited hepatic cholesterol biosynthesis with an inhibition of 82% at 25 mg/kg after 10 h, but the effect was no longer apparent at 21 h.
Inhibited cholesterol biosynthesis associated with an accumulation of radiolabeled diacid products in the liver.
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Animal Model:Sprague-Dawley rats (130-150 g)[1]
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Dosage:30 mg/kg
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Administration:p.o., b.i.d. for 2-4 days
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Result:Lowered serum cholesterol by 35% after 2 days and by nearly 50% after 3 days.
The reduction in cholesterol was greater in the very low-density lipoprotein (VLDL) and low-density lipoprotein (LDL) fractions (66-88%) than in the high-density lipoprotein (HDL) fraction (maximum, 35%).
Reduced serum triglycerides by up to 70%.
Induced hepatic microsomal HMG-CoA reductase activity by 12 to 34-fold.
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Animal Model:Sprague-Dawley rats (130-150 g) given a chow diet or the same diet supplemented with 2 % cholestyramine (HY-104081)[1]
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Dosage:30 mg/kg
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Administration:p.o., q.d. for 7 days
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Result:The R and S enantiomers reduced serum cholesterol by 9% and 24%, and triglycerides by 46% and 57%, respectively.
Coadministration with 2% cholestyramine in the diet reduced serum cholesterol by 49%.
The R enantiomer administered alone did not lower serum LDL cholesterol, whereas coadministration with cholestyramine resulted in a 30% reduction.
The reductions in LDL cholesterol with the S enantiomer in the absence and the presence of cholestyramine were 33% and 61%, respectively.
The reduction was greater in the VLDL and LDL fractions than in the HDL fraction.
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Animal Model:Male common marmosets (Callithrix jacchus)[1]
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Dosage:20 mg/kg
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Administration:p.o., b.i.d. for 7 days
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Result:Reduced plasma cholesterol by 50%.
The reduction in plasma cholesterol was selectively in the LDL fraction (≤50%), whereas cholesterol in the HDL fraction was unchanged.
Produced a greater reduction in plasma cholesterol than Lovastatin (HY-N0504) or Pravastatin (HY-B0165) (which produced ≤31% reduction at 50 mg/kg, b.i.d.).
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Animal Model:Male common marmosets (Callithrix jacchus)[1]
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Dosage:20 mg/kg
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Administration:p.o., q.d. for 7 days
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Result:Both enantiomers reduced total plasma cholesterol by approximately 27%.
The R and S enantiomers reduced LDL cholesterol by 50% and 43%, respectively.
Showed no significant changed in HDL cholesterol levels.
Chemical Information
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CAS No. 190841-57-7
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Masse moléculaire 403.34
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Formule C22H24Cl2N2O
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SMILES
OC1(C2=CC=C(C3=CC=C4N=CC=CC4=C3)C=C2)CN5CCC1CC5.Cl.Cl
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Livraison
Room temperature in continental US; may vary elsewhere.
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Stockage
Please store the product under the recommended conditions in the Certificate of Analysis.
Pureté et documentation
Références
[1]. Amin D, et al. RPR107393, a potent squalene synthase inhibitor and orally effective Cholesterol-lowering agent: comparison with inhibitors of HMG-CoA reductase. J Pharmacol Exp Ther. 1997 May;281(2):746-52. [Content Brief]
[2]. Hiyoshi H, et al. Squalene synthase inhibitors suppress triglyceride biosynthesis through the farnesol pathway in rat hepatocytes. J Lipid Res. 2003 Jan;44(1):128-35. [Content Brief]
Calculators
Concentration (start) × Volume (start) = Concentration (final) × Volume (final)
RPR107393 Related Classifications
HY-100299A Related Classifications
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