DISCOVERY OF YDROXYPROPYL]-(4S)-(4-HYDROXYPHENYL)-2-AZETIDINONE (SCH-58235) - A DESIGNED, POTENT, ORALLY-ACTIVE INHIBITOR OF CHOLESTEROL ABSORPTION

lpropyl)-1,(4S)-bis(4-methoxyphenyl)-2-azetidinone (2, SCH 48461), a n ovel inhibitor of intestinal cholesterol absorption, has recently been described by Burnett et al. and has been demonstrated to lower total plasma cholesterol in man. The potential sites of metabolism of 2 were considered, and the most probable metabolites were prepared. The oral cholesterol-lowering efficacy of the putative metabolites was evaluat ed in a 7-day cholesterol-fed hamster model for the reduction of serum total cholesterol and liver cholesteryl esters versus control. On the basis of our analysis of the putative metabolite structure-activity r elationship (SAR), SCH 58235 (1, droxypropyl]-(4S)-(4-hydroxyphenyl)-2 -azetidinone) was designed to exploit activity enhancing oxidation and to block sites of potential detrimental metabolic oxidation. Addition ally, a series of congeners of 2 were prepared incorporating strategic ally placed hydroxyl groups and fluorine atoms to further probe the SA R of 2-azetidinone cholesterol absorption inhibitors. Through the SAR analysis of a series of putative metabolites of 2, compound 1 was targ eted and found to exhibit remarkable efficacy with an ED50 of 0.04 mg/ kg/day for the reduction of liver cholesteryl esters in a 7-day choles terol-fed hamster model.