SYNTHESIS AND BIOLOGICAL-ACTIVITY OF NEW 3-HYDROXY-3-METHYLGLUTARYL-COA SYNTHASE INHIBITORS - 2-OXETANONES WITH A META-SUBSTITUENT ON THE BENZENE-RING IN THE SIDE-CHAIN

Isosteric side chain analogs of 3a were synthesized and tested for inh ibitory activities towards 3-hydroxy-3-methylglutaryl coenzyme A (HMG- CoA) synthase and upon cholesterol production in Hep G2 cells and in m ouse liver. It became clear that the lipophilic substituent on the aro matic ring and the terminal hydrophilic group in the side chain were i mportant in the enhancement of activity. Hexyloxyphenyl)ethyl]-3-hydro xy-methyl-2-oxetanone (5a) showed equivalent inhibitory activity in vi vo to that of 1233A.