Synthesis and Biological Activities of New HMG-CoA Synthase Inhibitors: 2-Oxetanones with a Side Chain Containing Biphenyl, Terphenyl or Phenylpyridine

A series of 1233A analogs containing biphenylyl, terphenylyl or phenylpyridyl groups in their side chain were synthesized and tested for the inhibitory activities against 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) synthase and inhibition for the cholesterol biosynthesis in the mouse liver. The compounds with an oxetane, cyclobutanone or γ-butyrolactone ring as isosters of a 2-oxetanone ring were entirely inactive. Among synthetic analogs, anti-4-[3-[2-(5-isopropyl-2-pyridyl)-ethyl]-phenyl]ethyl]-3hydroxymethyl-2-oxetanone (10b) was most active in vitro. The structure activity relationships on the transformations of 2-oxetanone and its side chain were obtained