title: Inhibitors of acyl-CoA:cholesterol acyltransferase. 5. Identification and structure-activity relationships of novel beta-ketoamides as hypocholesterolemic agents.
abstract: A study of structure-activity relationships of substituted beta-ketoamide ACAT inhibitors I and II was performed. The results of this study suggest that whereas the beta-keto group was tolerated with no loss in activity, beta-hydroxy and oxime moieties led to significantly reduced activity in vitro and in vivo. The most potent inhibitor from the acyclic series (I) (11, IC50 = 0.006 microM) contained a C-13 alkyl chain. This compound reduced plasma total cholesterol by 38% and 66% at 3 and 30 mg/kg, respectively, in cholesterol-fed rats. Dimethylation alpha to the anilide core (5) and subsequent N-methylation of the amide NH (6) decreased in vitro potency significantly. It was also found that high potency was retained with inhibitors which incorporated the carbonyl into a lactam ring (II).
authors.affiliation: Department of Medicinal Chemistry, Parke-Davis Pharmaceutical Research, Division of Warner-Lambert Company, Ann Arbor, Michigan 48105.
authors.forename: C E
authors.initials: CE
authors.lastname: Augelli-Szafran
authors.forename: C J
authors.initials: CJ
authors.lastname: Blankley
authors.forename: B D
authors.initials: BD
authors.lastname: Roth
authors.forename: B K
authors.initials: BK
authors.lastname: Trivedi
authors.forename: R F
authors.initials: RF
authors.lastname: Bousley
authors.forename: A D
authors.initials: AD
authors.lastname: Essenburg
authors.forename: K L
authors.initials: KL
authors.lastname: Hamelehle
authors.forename: B R
authors.initials: BR
authors.lastname: Krause
authors.forename: R L
authors.initials: RL
authors.lastname: Stanfield
mesh_terms: D000813:Anilides / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D000818:Animals; D000924:Anticholesteremic Agents / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D002784:Cholesterol / Q000097:blood; D007422:Intestines / Q000201:enzymology; D007659:Ketones / Q000737:chemistry*; D008297:Male; D008861:Microsomes / Q000201:enzymology; D011817:Rabbits; D051381:Rats; D017207:Rats, Sprague-Dawley; D002785:Sterol O-Acyltransferase / Q000037:antagonists & inhibitors*; D013329:Structure-Activity Relationship
chemical_list: D000813:Anilides; D000924:Anticholesteremic Agents; D007659:Ketones; C069304:PD 128042; D002784:Cholesterol; D002785:Sterol O-Acyltransferase