EFFECTS OF N-(4-METHYLBENZYLTHIOCARBONYL)-L-PHENYL-ALANINE (KF 1492), A NEW PHENYLALANINE DERIVATIVE, ON LIPID SYNTHESIS IN VIVO INHIBITION OF HEPATIC CHOLESTEROL SYNTHESIS AND 3-HYDROXY-3-METHYLGLUTARYL-CO A REDUCTASE

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KF 1492,a new phenylalanine derivative, was administered at a dose of 100 mg/kg or 0.25% (w/w) diet to Wistar rats. After different periods of drug administration, incorporation of ^<14>C-acetate or ^<14>C-mevalonic acid into digitonin-precipitable sterols and hepatic 3-hydroxy-3-methylglutaryl-Co A (HMG-CoA) reductase activity were measured. KF 1492 feeding was associated with depressed incorporation of ^<14>C-acetate into sterols in liver slices or homogenate. There was no effect on incorporation of ^<14>C-mevalonic acid into sterols. Thus, KF 1492 administration induced inhibition of hepatic HMG-CoA reductase correlated with reduction of incorporation of ^<14>C-acetate into digitonin-precipitable sterols. KF 1492 feeding also inhibited in vivo sterol synthesis in rats, which was intraperitoneally injected with ^<14>C-acetate. Stereoisomers, metabolites and chemically similar compounds of KF 1492 reduced HMG-CoA reductase activity, and this was correlated with lowering the activity of plasma cholesterol. These findings indicate that a major site of the action of KF 1492 in the inhibition of sterol synthesis may be at the level of HMG-CoA reductase.
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