title: Potent inhibitors of acyl-CoA:cholesterol acyltransferase. Structure-activity relationships of novel N-(4-oxochroman-8-yl)amides.
abstract: 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-dimethylpropanamid e (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 (61% at a dose of 0.1 mg/kg/day po).
authors.affiliation: Teijin Institute for Bio-Medical Research, Tokyo, Japan.
authors.forename: K
authors.initials: K
authors.lastname: Kataoka
authors.forename: T
authors.initials: T
authors.lastname: Shiota
authors.forename: T
authors.initials: T
authors.lastname: Takeyasu
authors.forename: T
authors.initials: T
authors.lastname: Mochizuki
authors.forename: K
authors.initials: K
authors.lastname: Taneda
authors.forename: M
authors.initials: M
authors.lastname: Ota
authors.forename: H
authors.initials: H
authors.lastname: Tanabe
authors.forename: H
authors.initials: H
authors.lastname: Yamaguchi
mesh_terms: D000818:Animals; D002784:Cholesterol / Q000097:blood; D003374:Coumarins / Q000737:chemistry / Q000494:pharmacology*; D005487:Foam Cells / Q000187:drug effects; D066298:In Vitro Techniques; D007413:Intestinal Mucosa / Q000201:enzymology; D008099:Liver / Q000378:metabolism; D008297:Male; D008861:Microsomes / Q000201:enzymology; D011817:Rabbits; D051381:Rats; D017208:Rats, Wistar; D002785:Sterol O-Acyltransferase / Q000037:antagonists & inhibitors*; D013329:Structure-Activity Relationship; D013379:Substrate Specificity
chemical_list: D003374:Coumarins; D002784:Cholesterol; D002785:Sterol O-Acyltransferase