Inhibition of cholesterol biosynthesis by fluorinated mevalonate analogues.

摘要: The conversion of mevalonate to cholesterol in rat liver homogenates (IC50 = 0.01-1.0 mM) is inhibited by 6- (I), 6,6-di- (II), and 6,6,6-trifluoromevalonate (III), as well 4,4-difluoromevalonate (IV). Addition compound I, III, or IV results the accumulation 5-phospho- 5-pyrophosphomevalonate. isopentenyl pyrophosphate not fluorinated analogues. It thus appears likely that decarboxylation 5-pyrophosphate inhibited. Rat catalyze phosphorylation I III. inhibition III was demonstrated directly with partially purified decarboxylase. Compound a remarkably effective inhibitor (Ki 10 nM). Similar were reported Nave et al. [Nave, J. F., d'Orchymont, H., Ducep, B., Piriou & Jung, M. (1985) Biochem. 227, 247]. phosphorylated pyrophosphorylated forms all inhibitors tested are responsible for inhibition. We also describe chemical method synthesis 5-pyrophosphate.