Pa. Procopiou et al., THE SQUALESTATINS - NOVEL INHIBITORS OF SQUALENE SYNTHASE - ENZYME-INHIBITORY ACTIVITIES AND IN-VIVO EVALUATION OF C1-MODIFIED ANALOGS, Journal of medicinal chemistry, 37(20), 1994, pp. 3274-3281
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.