THE SQUALESTATINS - DECARBOXY AND 4-DEOXY ANALOGS AS POTENT SQUALENE SYNTHASE INHIBITORS

Squalestatins without either the hydroxy group at C-4 or the carboxyli c acid at C-3 or C-4 were prepared and evaluated for their ability to inhibit rat liver microsomal squalene synthase (SQS) in vitro. These m odifications were well tolerated for compounds with the 4,6-dimethyloc tenoate ester at C-6 (S1 series). However in analogues without the C-6 ester (Hi series), removal of the C-4 hydroxy group gave compounds wi th reduced potency, whereas decarboxylation at C-3 resulted in a drama tic loss of SQS inhibitory activity. In comparison with S1 1, C-4 deox yS1 3 and C-3 decarboxyS1 10 have shorter in vivo durations of action on the inhibition of hepatic cholesterol biosynthesis in rats. C-4 deo xyS1 3 retains good serum cholesterol-lowering ability in marmosets, w hile C-3 decarboxyS1 10 showed only a marginal effect even at high dos e.