POTENT INHIBITORS OF ACYL-COA-CHOLESTEROL ACYLTRANSFERASE .2. STRUCTURE-ACTIVITY-RELATIONSHIPS OF NOVEL N-(2,2-DIMETHYL-2,3-DIHYDROBENZOFURAN-7-YL)AMIDES

Novel N-(2,2-dimethyl-2,3-dihydrobenzofuran-7-yl)amide derivatives 1 w ere synthesized and tested for their ability to inhibit rabbit small i ntestinal ACAT (acyl-CoA:cholesterol acyltransferase) and lower serum total cholesterol in cholesterol-fed rats. Among the synthesized compo unds, 2,4,6-tetramethyl-2,3-dihydrobenzofuran-7-yl)amide derivatives s howed potent ACAT inhibitory activity. The synthesis and structure-act ivity relationship of these compounds are described. A methyl group at position 6 of the 2,3-dihydrobenzofuran moiety was important for pote nt ACAT inhibitory activity. In the series of 4,6-tetramethyl-2,3-dihy drobenzofuran-7-yl)amides, lipophilicity of the acyl moiety was necess ary for the potent ACAT inhibitory activity. The highly lipophilic aci d amides 3-dihydrobenzofuran-7-yl)-2,2-dimethyldodecanamide (10) and - 2,3-dihdrobenzofuran-7-yl)-2,2-dimethylactanamide (50) showed potent a ctivity. Introduction of a dimethylamino group at position 5 of the 2, 3-dihydrobenzofuran moiety resulted in highly potent activity. The mos t potent compound, 3-dihydrobenzufuran-7-yl]-2,2-dimethyldodecanamide highly potent ACAT inhibitory activity (rabbit small intestine IC50 = 0.020 mu M, rabbit liver IC50 = 0.009 mu M), foam cell formation inhib itory activity (rat peritoneal macl rophage IC50 = 0.030 mu M), extrem ely potent serum cholesterol-lowering activity in cholesterol-fed rats (71% at a dose of 0.3 mg/kg/day po), and good bioavailability in fed dogs (C-max = 2.68 mu g/mL at 1 h, 10 mg/kg po).