THE SQUALESTATINS - INHIBITORS OF SQUALENE SYNTHASE - ENZYME-INHIBITORY ACTIVITIES AND IN-VIVO EVALUATION OF C3-MODIFIED ANALOGS

Squalestatin analogues modified at C3 were prepared and evaluated for their ability to inhibit rat liver microsomal squalene synthase in vit ro. While the 4,6-dimethyloctenoate ester group at C6 was maintained, a number of modifications to the C3 carboxylic acid were well tolerate d. However, in the absence of the C6 ester group, similar modification s to the C3 carboxyl group caused loss of activity. Selected compounds were evaluated for their ability to inhibit cholesterol biosynthesis in vivo in rats 1 and 6 h postadministration. Analogues of squalestati n 1 (S1) modified at C3 were found to possess a shorter duration of ef fect in vivo which is reflected in their substantially reduced ability to lower serum cholesterol levels in marmosets. Significant cholester ol lowering (up to 62%) for the C3 hydroxymethyl analogue Ib was obser ved only; when this compound was dosed three times a day for 3 days.