Azalanstat (RS-21607), a lanosterol 14α-demethylase inhibitor with cholesterol-lowering activity

Agents that inhibit hepatic cholesterol biosynthesis reduce circulating cholesterol levels in experimental animals and humans, and may be of pharmacological importance in the prevention of atherosclerosis. Azalanstat (RS-21607), a synthetic imidazole, has been shown to inhibit cholesterol synthesis...

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Veröffentlicht in:Biochemical pharmacology 1995-08, Vol.50 (4), p.529-544
Hauptverfasser: Burton, Pamela M., Swinney, David C., Heller, Renu, Dunlap, Bonnie, Chiou, Melody, Malonzo, Edna, Haller, Judy, Walker, Keith A.M., Salari, Amid, Murakami, Stanley, Mendizabal, Gregory, Tokes, Laszlo
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Sprache:eng
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Zusammenfassung:Agents that inhibit hepatic cholesterol biosynthesis reduce circulating cholesterol levels in experimental animals and humans, and may be of pharmacological importance in the prevention of atherosclerosis. Azalanstat (RS-21607), a synthetic imidazole, has been shown to inhibit cholesterol synthesis in HepG2 cells, human fibroblasts, hamster hepatocytes and hamster liver, by inhibiting the cytochrome P450 enzyme lanosterol 14α-demethyiase. When administered orally to hamsters fed regular chow, RS-21607 (50 mg/kg/day) lowered serum cholesterol in a dose-dependent manner (ED 50 = 62 mg/kg) in a period of 1 week. It preferentially lowered low density lipoprotein (LDL) cholesterol and apo B relative to high density lipoprotein (HDL) cholesterol and apo A-1. It also lowered plasma cholesterol levels in hamsters fed a high saturated fat and cholesterol diet. RS-21607 inhibited hepatic microsomal hydroxymethylglutaryl-CoA (HMG-CoA) reductase activity in hamsters in a dosedependent manner (ED 50 = 31 mg/kg), and this was highly correlated with serum cholesterol lowering ( r = 0.97). Cholesterol lowering by azalanstat and cholestyramine was additive, and the increase in HMG-CoA reductase brought about by cholestyramine was attenuated significantly by azalanstat. In vitro studies with HepG2 cells indicated that this modulation of reductase activity was indirect, occurring at a post-transcriptional step, and it is proposed that a regulatory oxysterol derived from dihydrolanosterol (or lanosterol) may be responsible for this regulation. Azalanstat does not appear to lower circulating cholesterol in the hamster by up-regulation of the hepatic LDL receptor, suggesting that other mechanisms are involved. Orally administered azalanstat (50–75 mg/kg) stimulated hepatic microsomal cholesterol 7α-hydroxylase activity by 50–400% in hamsters, and it is postulated that this may result from modified cholesterol absorption and bile acid synthesis.
ISSN:0006-2952
1873-2968
DOI:10.1016/0006-2952(95)00152-P