174583-24-5Relevant articles and documents
Acyl-CoA:cholesterol O-acyltransferase (ACAT) inhibitors. 2. 2-(1,3- dioxan-2-yl)-4,5-diphenyl-1H-imidazoles as potent inhibitors of ACAT
Astles,Ashton,Bridge,Harris,Hart,Parrott,Porter,Riddell,Smith,Williams
, p. 1423 - 1432 (1996)
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 50 = 10 nM) which contain lipophilic terminal heterocycles do not appear to be systemically available. Less patent 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.
