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

1995; Elsevier BV; Volume: 50; Issue: 4 Linguagem: Inglês

10.1016/0006-2952(95)00152-p

1873-2968

Pamela M. Burton, David C. Swinney, Renu Heller, Bonnie Dunlap, Melody Chiou, Edna Malonzo, Judy Haller, Keith A. M. Walker, Amid Salari, Stanley Murakami, Gregory Mendizabal, L Tökès,

Inflammatory mediators and NSAID effects

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 (ED50 = 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 (ED50 = 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.