Azalanstat mesylate
Azalanstat (RS-21607) mesylate is an orally active lanosterol 14α-demethylase inhibitor. Azalanstat mesylate exerts a cholesterol-lowering effect by inhibiting cholesterol synthesis and regulating HMG-CoA Reductase (HMGCR), and shows an additive effect when used in combination with Cholestyramine (HY-104081). Azalanstat mesylate is used in the study of hypercholesterolemia.
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- CAS No.: 143484-80-4
- Formule: C23H28ClN3O5S2
- Masse moléculaire:526.07
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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
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Activité biologique
Description
Cellular Effect
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Cell Line
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Type | Value | Description | References |
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| Fibroblast | IC50 |
0.2 nM
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Inhibition of cholesterol synthesis (measured via [14C]-acetate incorporation into demethyl-sterol/cholesterol fraction) in human fibroblasts, with 1 hr pre-incubation followed by 2 hr pulse with [14C] sodium acetate.
Inhibition of cholesterol synthesis (measured via [14C]-acetate incorporation into demethyl-sterol/cholesterol fraction) in human fibroblasts, with 1 hr pre-incubation followed by 2 hr pulse with [14C] sodium acetate.
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7646560 |
| HepG2 | IC50 |
6.5 nM
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Inhibition of cholesterol synthesis (measured via [14C]-acetate incorporation into demethyl-sterol/cholesterol fraction) in HepG2 cells, with 1 hr pre-incubation followed by 2 hr pulse with [14C] sodium acetate.
Inhibition of cholesterol synthesis (measured via [14C]-acetate incorporation into demethyl-sterol/cholesterol fraction) in HepG2 cells, with 1 hr pre-incubation followed by 2 hr pulse with [14C] sodium acetate.
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7646560 |
In Vitro
Azalanstat (RS-21607) (0.1 nM-10 μM; 1 h pre-incubation, 2 h pulse) mesylate potently inhibits cholesterol synthesis in human fibroblasts (IC50 = 0.2 nM), HepG2 cells (IC50 = 6.5 nM), and hamster hepatocytes (IC50 = 10 nM) by inhibiting lanosterol 14α-demethylase, which leads to the accumulation of methyl sterols without the accumulation of oxidosqualene[1].
Azalanstat (0.01-100 μM; 20 h) mesylate exerts a biphasic regulatory effect on HMG-CoA reductase activity in HepG2 cells: it inhibits approximately 40% of the enzyme activity at concentrations of 0.01-1 μM, and stimulates enzyme activity up to 600% at concentrations of 30-100 μM[1].
Azalanstat (0.1-5 μM; 18 h) mesylate increases HMG-CoA reductase mRNA levels by 300% at 0.1 μM and by 100% at 5 μM in HepG2 cells, and elevates LDL receptor mRNA levels by 70% at both 0.1 μM and 5 μM, suggesting post-transcriptional regulation of HMG-CoA reductase activity[1].
Azalanstat (0.1-10 μM; 24 h pre-incubation, 3 h LDL uptake) mesylate increases specific 125I-LDL uptake by approximately 25% in HepG2 cells[1].
Azalanstat (0.1-100 μM; 10 min pre-incubation, 15 min total incubation at 37 °C) mesylate moderately inhibits rat spleen HO-1 (IC50 = 5.3 μM) and rat brain HO-2 (IC50 = 24.5 μM), with a 4.6-fold selectivity for HO-1 over HO-2[3].
MedChemExpress (MCE) has not independently confirmed the accuracy of these methods. They are for reference only.
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Cell Line:human fibroblasts, HepG2 cells, hamster hepatocytes
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Concentration:0.1, 1.0, 10, 100, 1000, 10000 nM
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Incubation Time:1 hr pre-incubation, 2 hr pulse
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Result:Inhibited cholesterol synthesis in human fibroblasts (IC50 = 0.2 nM), HepG2 cells (IC50 = 6.5 nM), and hamster hepatocytes (IC50 = 10 nM) by blocking lanosterol 14α-demethylase.
In Vivo
Azalanstat (50 mg/kg; oral; once daily; for 28 days) mesylate reduces plasma cholesterol by 37% in hamsters fed a high-fat/high-cholesterol diet, and its effect is transiently maintained after drug withdrawal[1].
Azalanstat (50 mg/kg; oral; once daily; for 14 consecutive days) mesylate inhibits cholesterol synthesis in hamster tissues by up to 98%. It exhibits no selectivity in tissue distribution and also elevates methyl sterol levels, particularly dihydrolanosterol levels in the liver[1].
Azalanstat (25-100 mg/kg; oral; daily; 14 days) mesylate inhibits hepatic microsomal HMG-CoA reductase activity in a dose-dependent manner in hamsters, with an ED50 of 31 mg/kg, and this activity is highly correlated with serum cholesterol reduction[1].
Azalanstat (50-75 mg/kg; oral; daily; for 1-2 weeks) mesylate increases hepatic cholesterol 7α-hydroxylase activity in hamsters by 1.5- to 5-fold, and this effect emerges after 1-2 weeks of oral administration at a dose of 50-75 mg/kg[1].
Azalanstat (30 mg/kg; p.o.; once daily; for 7 consecutive days) mesylate reduces serum cholesterol in hamsters by 44% and inhibits hepatic HMG-CoA reductase activity; its cholesterol-lowering effect exerts a synergistic effect with Cholestyramine (HY-104081), and it also attenuates Cholestyramine-induced activation of HMG-CoA reductase[1].
Azalanstat (50 mg/kg; oral; daily; 7-10 days) mesylate reduces liver-specific LDL binding capacity and LDL receptor protein expression levels in hamsters, while lowering serum cholesterol by up to 53%[1].
MedChemExpress (MCE) has not independently confirmed the accuracy of these methods. They are for reference only.
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Animal Model:Golden Syrian hamsters (male, 90-110 g, fed regular Purina Rodent Chow 5001 containing 0.027% cholesterol)[1]
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Dosage:25 mg/kg; 50 mg/kg; 75 mg/kg; 100 mg/kg
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Administration:p.o.; daily; 14 days
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Result:Lowered serum cholesterol in a dose-dependent manner with an ED50 of 62 mg/kg.
Reduced total cholesterol to 91.2 mg/dL, LDL cholesterol to 13.2 mg/dL, apo B to 17.3 mg/dL, and increased the HDL/total cholesterol ratio to 63.4%, while increasing the apo A-1/apo B ratio to 6.5 at 25 mg/kg.
Reduced total cholesterol to 71.8 mg/dL, LDL cholesterol to 9.9 mg/dL, apo B to 15.4 mg/dL, triglycerides to 185.8 mg/dL, increased the HDL/total cholesterol ratio to 66.3%, and increased the apo A-1/apo B ratio to 6.8 at 50 mg/kg.
Reduced total cholesterol to 66.5 mg/dL, LDL cholesterol to 3.5 mg/dL, apo B to 9.1 mg/dL, increased the HDL/total cholesterol ratio to 71.4%, and increased the apo A-1/apo B ratio to 10.0 at 75 mg/kg.
Reduced total cholesterol to 60.7 mg/dL, LDL cholesterol to 6.1 mg/dL, apo B to 11.7 mg/dL, triglycerides to 177.4 mg/dL, increased the HDL/total cholesterol ratio to 68.2%, and increased the apo A-1/apo B ratio to 8.2 at 100 mg/kg.
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Animal Model:Golden Syrian hamsters (male, 90-110 g, fed high fat diet containing 0.1% cholesterol, 5.9% butter fat, and 6% peanut oil for 4 weeks)[1]
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Dosage:50 mg/kg
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Administration:p.o.; daily; 28 days
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Result:Reduced plasma cholesterol by 37% within 2 weeks.
Maintained plasma cholesterol levels significantly lower than controls for 2 weeks after treatment termination.
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Animal Model:Golden Syrian hamsters (male, 90-110 g, fed regular Purina Rodent Chow 5001)[1]
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Dosage:50 mg/kg
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Administration:p.o.; daily; 14 days
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Result:Inhibited cholesterol (demethyl-sterol) synthesis by 98% in liver, 95% in kidney, 87% in spleen, 38% in adrenals, 93% in testes, and 95% in small intestine.
Increased methyl-sterol synthesis in all tested tissues.
Elevated hepatic dihydrolanosterol levels ~100-fold.
Raised serum dihydrolanosterol to 0.78 mg/dL.
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Animal Model:Golden Syrian hamsters (male, 90-110 g, fed regular Purina Rodent Chow 5001)[1]
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Dosage:25 mg/kg; 50 mg/kg; 75 mg/kg; 100 mg/kg
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Administration:p.o.; daily; 14 days
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Result:Suppressed hepatic microsomal HMG-CoA reductase activity in a dose-dependent manner with an ED50 of 31 mg/kg.
Showed a strong correlation between serum cholesterol levels and hepatic HMG-CoA reductase activity.
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Animal Model:Golden Syrian hamsters (male, 90-110 g, fed regular Purina Rodent Chow 5001)[1]
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Dosage:50 mg/kg; 75 mg/kg
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Administration:p.o.; daily; 7-14 days
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Result:Induced hepatic cholesterol 7α-hydroxylase activity by 149% at 50 mg/kg for 1 week.
Induced hepatic cholesterol 7α-hydroxylase activity by 235% at 50 mg/kg for 2 weeks.
Induced hepatic cholesterol 7α-hydroxylase activity by 501% at 75 mg/kg for 2 weeks.
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Animal Model:Golden Syrian hamsters (male, 90-110 g, fed regular Purina Rodent Chow 5001)[1]
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Dosage:30 mg/kg; 30 mg/kg plus cholestyramine 500 mg/kg
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Administration:p.o.; daily; 7 days; p.o.; twice daily; 7 days (cholestyramine)
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Result:Reduced serum cholesterol by 44% and suppressed hepatic HMG-CoA reductase activity to 44% of control levels when administered alone.
Reduced serum cholesterol by 58% and attenuated cholestyramine-induced increase in HMG-CoA reductase activity to 171% of control levels when coadministered with cholestyramine.
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Animal Model:Golden Syrian hamsters (male, 90-110 g, fed regular Purina Rodent Chow 5001)[1]
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Dosage:50 mg/kg
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Administration:p.o.; daily; 7-10 days
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Result:Reduced specific 125I-LDL binding to hepatic membranes to 38% of control levels and reduced serum cholesterol by 41% after 7 days.
Reduced LDL receptor protein expression to 51% of control levels and reduced serum cholesterol by 53% after 10 days.
Chemical Information
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CAS No. 143484-80-4
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Masse moléculaire 526.07
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Formule C23H28ClN3O5S2
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SMILES
CS(=O)(O)=O.ClC(C=C1)=CC=C1CC[C@]2(O[C@@H](CO2)CSC3=CC=C(C=C3)N)CN4C=CN=C4
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Synonyms
RS-21607 mesylate
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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
Calculators
Concentration (start) × Volume (start) = Concentration (final) × Volume (final)
Azalanstat mesylate Related Classifications
HY-105191C Related Classifications
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Keywords
- Azalanstat
- 143484-80-4
- RS-21607
- RS21607
- RS 21607
- CETP
- HMG-CoA Reductase (HMGCR)
- mouse blastocyst
- heme oxygenase-2
- heme oxygenase-1
- hamster hepatocytes
- hepatic microsomal cholesterol 7α-hydroxylase
- lanosterol 14α-demethylase
- hypercholesterolemia
- human fibroblasts
- hepatic microsomal HMG-CoA reductase
- HepG2 cells
- Inhibitor
- inhibitor
- inhibit