Potent Inhibitors of Acyl-CoA:Cholesterol Acyltransferase. Structure-Activity Relationships of Novel N-(4-Oxochroman-8-yl)amides

Article abstract of DOI:10.1021/jm00016a021

Novel N-(4-oxochroman-8-yl)amide derivatives 1 were synthesized and tested for their ability to inhibit rabbit small intestinal ACAT (acyl-CoA:cholesterol acyltransferase) in vitro and to lower serum total cholesterol in cholesterol-fed rats in vivo.Among the synthesized compounds, 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 compounds are discussed on the basis of these two assays.The carbonyl group at position 4 of the 4-chromanone was essential for potent ACAT inhibitory 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 necessary factor to elicit the potent ACAT inhibitory activity was lipophilicity of the molecules.The highly lipophilic acid amides N-(7-methoxy-4-oxochroman-8-yl)-2,2-dimethyldodecanamide (35) and 4-<<6-(4-chlorophenoxy)hexyl>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 this case, highest inhibitory activity was obtained by N-<7-(decyloxy)-4-oxochroman-8-yl>-2,2-dimethylpropanamide (65).The most potent compound, N-(7-methoxy-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 activity (rat peritoneal macrophage IC₅₀ = 160 nM), and extremely potent serum cholesterol-lowering activity in cholesterol-fed rats (61percent at a dose of 0.1 mg/kg/day po).