title: Acyl-CoA:Cholesterol O-acyltransferase (ACAT) inhibitors. 2. 2-(1,3-Dioxan-2-yl)-4,5-diphenyl-1H-imidazoles as potent inhibitors of ACAT.
abstract: The second in this series of papers concerns our further investigations into the search for a potent bioavailable acyl-CoA:cholesterol O-acyltransferase (ACAT) inhibitor suitable for the treatment of atherosclerosis. The design, synthesis, and structure-activity relationship for a series of ACAT inhibitors based on the 2-(1,3-dioxan-2-yl)-4,5-diphenyl-1H-imidazole pharmacophore are described. Compounds such as 13a bearing simple alkyl or hydroxymethyl substituents at the 5-position of the 1,3-dioxane ring are potent bioavailable inhibitors of the rat hepatic microsomal enzyme in vitro (IC50 < 100 nM) but are only weak inhibitors of the human hepatic enzyme. We have found however that 1,3-dioxanes substituted at the 5-cis position with pyrazolylalkyl or aminoalkyl groups are potent inhibitors in vitro of human macrophage ACAT, the potency depending on the nature of the terminal heterocycle and the length of the alkyl chain. An ex vivo bioassay herein demonstrates that potent inhibitors such as 13t (IC50 = 10 nM) which contain lipophilic terminal heterocycles do not appear to be systematically available. Less potent but more water soluble compounds such as 13h (IC50 = 60 nM) and 13n (IC50 = 70 nM) are absorbed following oral dosing and achieve plasma levels significantly in excess of their IC50 for ACAT inhibition. These compounds are therefore possible candidates for further investigation as oral antiatherosclerotic agents.
authors.affiliation: Rhône-Poulenc Rorer, Dagenham Research Centre, Dagenham, Essex, U.K.
authors.forename: P C
authors.initials: PC
authors.lastname: Astles
authors.forename: M J
authors.initials: MJ
authors.lastname: Ashton
authors.forename: A W
authors.initials: AW
authors.lastname: Bridge
authors.forename: N V
authors.initials: NV
authors.lastname: Harris
authors.forename: T W
authors.initials: TW
authors.lastname: Hart
authors.forename: D P
authors.initials: DP
authors.lastname: Parrott
authors.forename: B
authors.initials: B
authors.lastname: Porter
authors.forename: D
authors.initials: D
authors.lastname: Riddell
authors.forename: C
authors.initials: C
authors.lastname: Smith
authors.forename: R J
authors.initials: RJ
authors.lastname: Williams
mesh_terms: D000818:Animals; D001161:Arteriosclerosis / Q000188:drug therapy; D001682:Biological Availability; D004146:Dioxanes / Q000138:chemical synthesis / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D006801:Humans; D007093:Imidazoles / Q000138:chemical synthesis / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D008264:Macrophages / Q000201:enzymology; D009682:Magnetic Resonance Spectroscopy; D008862:Microsomes, Liver / Q000201:enzymology; D015394:Molecular Structure; D011817:Rabbits; D051381:Rats; D002785:Sterol O-Acyltransferase / Q000037:antagonists & inhibitors*; D013329:Structure-Activity Relationship
chemical_list: D004146:Dioxanes; D004791:Enzyme Inhibitors; D007093:Imidazoles; D002785:Sterol O-Acyltransferase