INHIBITORS OF ACYL-COA-CHOLESTEROL O-ACYLTRANSFERASE - 3 - DISCOVERY OF A NOVEL SERIES OF N-ALKYL-N-[(FLUOROPHENOXY)BENZYL]-N'-ARYLUREAS WITH WEAK TOXICOLOGICAL EFFECTS OF ADRENAL-GLANDS

A series of N-alkyl-N-[(fluorophenoxy)benzyl] -N'-arylureas were prepa red and evaluated for their ability to inhibit intestinal acyl-CoA:cho lesterol O-acyltransferase and to inhibit accumulation of cholesteryl esters in macrophages in vitro. In vivo hypocholesterolemic activity w as assessed in cholesterol-fed rats by oral administration as a dietar y admixture and/or by gavage in a PEG400 vehicle. Modification of the alkyl substituent on the N'-aryl moiety and on the urea nitrogen signi ficantly influenced macrophage assay in vitro. Toxicological study rev ealed a distinct relationship between macrophage assay and the toxicit y observed in adrenal glands of rabbits treated with representatives o f this series of compounds. Investigations utilizing the macrophage as say as an indicator for adrenal toxicity led to the identification of compounds 1g (FR190809) and 1k (FR186485, or FR195249 as its hydrochlo ride salt) as potent, nonadrenotoxic, orally efficacious ACAT inhibito rs irrespective of the administration method.