A novel series of N-(1-phenyl-2-benzimidazolyl)-N'-phenylurea derivatives were prepared as ACAT inhibitors. These compounds showed potent ACAT inhibitory activity in vitro (liver microsomes from cholesterol-fed rabbits) and hypocholesterolemic activity in vivo (cholesterol-fed golden hamsters).
Acyl-CoA:cholesterol acyltransferase (ACAT, EC 2.3.1.26) is a primary enzyme responsible for the intracellular esterification of free cholesterol. This enzyme is thought to play a key role in intestinal absorption of dietary cholesterol, hepatic production of lipoproteins and the accumulation of cholesteryl esters in the arterial lesions. 1 Inhibition of this enzyme would thus be expected to reduce plasma cholesterol concentration, to reduce the secretion of very low density lipoproteins (VLDL) into the plasma, and to prevent the formation of foam cells in the arterial walls. Therefore, ACAT inhibitors offer potential as hypocholesterolemic and antiatherosclerotic agents. 2
Recently, a number of potent ACAT inhibitors, of widely diverse structures, have been described. 3 Typically, they consist of two lipophilic moieties linked with an amide or a urea and most of them are highly lipophilic. In the course of our investigation to find novel ACAT inhibitors, we attempted to introduce heterocycles to improve in the lipophilicity and synthesized a series of N-(1-phenyl-2-benzimidazolyl)-N'-phenylurea derivatives. 4
Compounds prepared were tested for their ability to inhibit ACAT in vitro and to decrease serum total cholesterol in vivo. In the present paper, we have described the synthesis, structure-activity relationships and biological evaluation of this novel class of ACAT inhibitors.