The squalestatins: inhibitors of squalene synthase. Enzyme inhibitory activities and in vivo evaluation of C3-modified analogues.

Squalestatin analogues modified at C3 were prepared and evaluated for their ability to inhibit rat liver microsomal squalene synthase in vitro. While the 4,6-dimethyloctenoate ester group at C6 was maintained, a number of modifications to the C3 carboxylic acid were well tolerated. However, in the absence of the C6 ester group, similar modifications 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 squalestatin 1 (S1) modified at C3 were found to possess a shorter duration of effect in vivo which is reflected in their substantially reduced ability to lower serum cholesterol levels in marmosets. Significant cholesterol lowering (up to 62%) for the C3 hydroxymethyl analogue 1b was observed only when this compound was dosed three times a day for 3 days.