POTENT INHIBITORS OF ACYL-COA-CHOLESTEROL ACYLTRANSFERASE - STRUCTURE-ACTIVITY-RELATIONSHIPS OF NOVEL N-(4-OXOCHROMAN-8-YL)AMIDES

Novel N-(4-oxochroman-8-yl)amide derivatives 1 were synthesized and te sted for their ability to inhibit rabbit small intestinal ACAT (acyl-C oA:cholesterol acyltransferase) in vitro and to lower serum total chol esterol in cholesterol-fed rats in vivo. Among the synthesized compoun ds, N-(7-alkoxy-4-oxochroman-8-yl)amide derivatives showed potent ACAT inhibitory activity both in vitro and in vivo. The structure-activity relationships of these N-(4-oxochroman-8-yl)amides and related compou nds are discussed on the basis of these two assays. The carbonyl group at position 4 of the 4-chromanone was essential for potent ACAT inhib itory activity. N-(Chromon-8-yl) derivatives were less potent than N-( 4-oxochroman-8-yl) derivatives. An alkoxy-group at position 7 of the 4 -chromanone moiety was important for potent ACAT inhibitory activity. In the N-(7-alkoxy-4-oxochroman-8-yl)amide derivatives, another necess ary factor to elicit the potent ACAT inhibitory activity was lipophili city of the molecules. The highly lipophilic acid amides ethoxy-4-oxoc hroman-8-yl)-2,2-dimethyldodecanamide (35) and exyl]oxy]-N-(7-methoxy- 4-oxochroman-8-yl)benzamide (63) showed potent activity. Introduction of a highly lipophilic alkoxy group at position 7 of the 4-chromanone moiety instead of methoxy group also resulted in potent activity. In t his case, highest inhibitory activity was obtained by cyloxy)-4-oxochr oman-8-yl]-2,2-dimethylpropanamide (65). The most potent compound, eth oxy-4-oxochroman-8-yl)-2,2-dimethyldodecanamide (35, TEI-6522), showed . significant ACAT inhibitory activity (rabbit small intestine IC50 = 13 nM, rabbit liver IC50 = 16 nM), foam cell formation inhibitory acti vity (rat peritoneal macrophage IC50 = 160 nM), and extremely potent s erum cholesterol-lowering activity in cholesterol-fed rats (61% at a d ose of 0.1 mg/kg/day po).(1)