THE SQUALESTATINS - NOVEL INHIBITORS OF SQUALENE SYNTHASE - ENZYME-INHIBITORY ACTIVITIES AND IN-VIVO EVALUATION OF C1-MODIFIED ANALOGS

Squalestatin analogues modified in the C1 side chain were prepared and evaluated for their ability to inhibit rat liver microsomal and Candi da squalene synthase (SQS) in vitro. While maintaining the 4,6-dimethy loctenoate or 4,6-dimethyloctanoate ester groups at C6, a number of mo difications to the C1 side chain were well tolerated. However, in the absence of the C6 ester group, similar modifications to the C1 side ch ain caused substantial loss of activity. Compounds were also evaluated for their ability to inhibit cholesterol biosynthesis in vivo in rats and to reduce serum cholesterol levels in marmosets. These studies re vealed that compounds with similar SQS inhibitory activities can posse ss different in vivo durations of action and lipid-lowering abilities.