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Updated: Jul 30, 2026
09:15
Differential Effects of Lipid-lowering Drugs in Modulating Morphology of Cholesterol Particles
Published on: November 10, 2017
Azalanstat (RS-21607), a lanosterol 14 alpha-demethylase inhibitor with cholesterol-lowering activity
P M Burton1, D C Swinney, R Heller
1Institute of Biochemistry and Cell Biology, Syntex Research, Palo Alto, CA 94304, USA.
Biochemical Pharmacology
|August 8, 1995
Summary
Azalanstat (RS-21607) effectively lowers cholesterol by inhibiting hepatic cholesterol synthesis in hamsters. This synthetic imidazole reduces LDL cholesterol and apo B, offering potential for atherosclerosis prevention.
Area of Science:
- Pharmacology
- Biochemistry
- Cardiovascular Research
Background:
- Inhibiting hepatic cholesterol biosynthesis is a key strategy for reducing circulating cholesterol and preventing atherosclerosis.
- Azalanstat (RS-21607), a synthetic imidazole, targets cholesterol synthesis by inhibiting lanosterol 14 alpha-demethylase, a cytochrome P450 enzyme.
Purpose of the Study:
- To evaluate the efficacy of Azalanstat (RS-21607) in lowering cholesterol levels in experimental models.
- To investigate the mechanism of action of Azalanstat in modulating cholesterol metabolism and related enzyme activities.
Main Methods:
- Oral administration of Azalanstat to hamsters on regular and high-fat/cholesterol diets.
- Measurement of serum cholesterol, LDL cholesterol, HDL cholesterol, apo B, and apo A-1 levels.
- Assay of hepatic microsomal hydroxymethylglutaryl-CoA (HMG-CoA) reductase and cholesterol 7 alpha-hydroxylase activities.
- In vitro studies using HepG2 cells to elucidate the mechanism of reductase modulation.
Main Results:
- Azalanstat dose-dependently lowered serum cholesterol in hamsters (ED50 = 62 mg/kg), preferentially reducing LDL cholesterol and apo B.
- Inhibition of hepatic HMG-CoA reductase activity (ED50 = 31 mg/kg) strongly correlated with cholesterol lowering (r = 0.97).
- Azalanstat demonstrated additive cholesterol-lowering effects with cholestyramine and attenuated cholestyramine-induced HMG-CoA reductase increases.
- Stimulation of hepatic cholesterol 7 alpha-hydroxylase activity was observed, suggesting effects on cholesterol absorption and bile acid synthesis.
Conclusions:
- Azalanstat is an effective agent for lowering circulating cholesterol and LDL cholesterol in hamsters through inhibition of hepatic cholesterol biosynthesis.
- The mechanism involves indirect, post-transcriptional modulation of HMG-CoA reductase activity and stimulation of cholesterol 7 alpha-hydroxylase.
- Azalanstat's distinct mechanism, not involving LDL receptor up-regulation, suggests potential as a therapeutic agent for atherosclerosis.
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