A comparison of the inhibition of yeast, rat, and human squalene synth
etase (SQS) by zaragozic acid C and two farnesyl pyrophosphate (FPP) a
nalogs was made. IC50 values measured at steady state revealed that za
ragozic acid C was a nanomolar inhibitor of all three isozymes. The is
oprenoid (phosphinylmethyl) phosphonate (266056), an FPP analog which
has the allylic and anhydride oxygen atoms replaced with CH2, was a mi
cromolar inhibitor of all three isozymes. An exception to the above tr
ends was seen with an ether-linked (phosphinylmethyl) phosphonate (267
338). This compound was between 15- and 42-fold more potent an inhibit
or of the mammalian forms of SQS than it was for yeast squalene synthe
tase, suggesting potential differences in active-site binding residues
. (C) 1994 Academic Press, Inc.