title: Acyl-CoA:cholesterol O-acyl transferase (ACAT) inhibitors. 1. 2-(Alkylthio)-4,5-diphenyl-1H-imidazoles as potent inhibitors of ACAT.
abstract: A potent, bioavailable ACAT inhibitor may have beneficial effects in the treatment of atherosclerosis by (i) reducing the absorption of dietary cholesterol, (ii) reducing the secretion of very low density lipoproteins into plasma from the liver, and (iii) preventing the transformation of arterial macrophages into foam cells. We have found that a mevalonate derivative 2, which contains a 4,5-diphenyl-1H-imidazol-2-yl moiety, inhibits rat hepatic microsomal ACAT in vitro and produces a significant hypocholesterolemic effect in the cholesterol-fed rat. Structure-activity relationships for analogues of 2 demonstrate that the 4,5-diphenyl-1H-imidazole moiety is a pharmacophore for inhibition of rat microsomal ACAT.
authors.affiliation: Rhone-Poulenc Rorer, Central Research, Dagenham, Essex, U.K.
authors.forename: N V
authors.initials: NV
authors.lastname: Harris
authors.forename: C
authors.initials: C
authors.lastname: Smith
authors.forename: M J
authors.initials: MJ
authors.lastname: Ashton
authors.forename: A W
authors.initials: AW
authors.lastname: Bridge
authors.forename: R C
authors.initials: RC
authors.lastname: Bush
authors.forename: E C
authors.initials: EC
authors.lastname: Coffee
authors.forename: D I
authors.initials: DI
authors.lastname: Dron
authors.forename: M F
authors.initials: MF
authors.lastname: Harper
authors.forename: D J
authors.initials: DJ
authors.lastname: Lythgoe
authors.forename: C G
authors.initials: CG
authors.lastname: Newton
mesh_terms: D000818:Animals; D000924:Anticholesteremic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D007093:Imidazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D008297:Male; D008862:Microsomes, Liver / Q000187:drug effects / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D002785:Sterol O-Acyltransferase / Q000037:antagonists & inhibitors*; D013329:Structure-Activity Relationship
chemical_list: D000924:Anticholesteremic Agents; D007093:Imidazoles; D002785:Sterol O-Acyltransferase