ACYL-COA-CHOLESTEROL O-ACYLTRANSFERASE (ACAT) INHIBITORS .2. 2-(1,3-DIOXAN-2-YL)-4,5-DIPHENYL-1H-IMIDAZOLES AS POTENT INHIBITORS OF ACAT

The second in this series of papers concerns our further investigation s into the search for a potent bioavailable acyl-CoA:cholesterol O-acy ltransferase (ACAT) inhibitor suitable for the treatment of atheroscle rosis. The design, synthesis, and structure-activity relationship for a series of ACAT inhibitors based on the 2-(1,3-dioxan-2-yl)-4,5-diphe nyl-1H-imidazole pharmacophore are described. Compounds such as 13a be aring simple alkyl or hydroxymethyl substituents at the 5-position of the 1,3-dioxane ring are potent bioavailable inhibitors of the rat hep atic microsomal enzyme in vitro (IC50 < 100 nM) but are only weak inhi bitors of the human hepatic enzyme. We have found however that 1,3-dio xanes substituted at the 5-cis position with pyrazolylalkyl or aminoal kyl groups are potent inhibitors in vitro of human macrophage ACAT, th e potency depending on the nature of the terminal heterocycle and the length of the alkyl chain. An ex vivo bioassay described herein demons trates that potent inhibitors such as 13t (IC50 = 10 nM) which contain lipophilic terminal heterocycles do not appear to be systemically ava ilable. Less potent but more water soluble compounds such as 13h (IC50 = 60 nM) and 13n (IC50 = 70 nM) are absorbed following oral dosing an d achieve plasma levels significantly in excess of their IC50 for ACAT inhibition. These compounds are therefore possible candidates for fur ther investigation as oral antiatherosclerotic agents.