title: Inhibitors of acyl-CoA:cholesterol O-acyltransferase. 11. Structure-activity relationships of several series of compounds derived from N-(chlorocarbonyl) isocyanate.
abstract: Five series of compounds (4-9) derived from N-(chlorocarbonyl) isocyanate have been synthesized and evaluated for their ability to inhibit the enzyme acyl-CoA:cholesterol O-acyltransferase and lower plasma cholesterol levels in cholesterol-fed rats. Structure-activity relationships indicate that the imino dicarboxylates (6 and 7) and the oxycarbonyl thiocarbamates (8) are the most potent and efficacious series. In these series, the combination of a 2,6-diisopropylphenyl group and an aliphatic alkyl group with a chain length between 6 and 14 carbon atoms gives good activity in vitro and in vivo. In addition, a hydrogen donor is required to maintain good in vitro activity, and the acidic proton on the central nitrogen in these series appears to be important for in vivo activity.
authors.affiliation: Department of Medicinal Chemistry, parke-Davis Pharmaceutical Research, Division of Warner-Lambert Company, Ann Arbor, Michigan 48105.
authors.forename: J A
authors.initials: JA
authors.lastname: Picard
authors.forename: R F
authors.initials: RF
authors.lastname: Bousley
authors.forename: H T
authors.initials: HT
authors.lastname: Lee
authors.forename: K L
authors.initials: KL
authors.lastname: Hamelehle
authors.forename: B R
authors.initials: BR
authors.lastname: Krause
authors.forename: L L
authors.initials: LL
authors.lastname: Minton
authors.forename: D R
authors.initials: DR
authors.lastname: Sliskovic
authors.forename: R L
authors.initials: RL
authors.lastname: Stanfield
mesh_terms: D000818:Animals; D002784:Cholesterol / Q000097:blood; D000960:Hypolipidemic Agents / Q000737:chemistry / Q000494:pharmacology*; D017953:Isocyanates / Q000737:chemistry / Q000494:pharmacology*; D051381:Rats; D002785:Sterol O-Acyltransferase / Q000037:antagonists & inhibitors*; D013329:Structure-Activity Relationship
chemical_list: D000960:Hypolipidemic Agents; D017953:Isocyanates; D002784:Cholesterol; D002785:Sterol O-Acyltransferase