Novel Aryloxyalkylthioimidazoles as Inhibitors of Acyl-CoA: Cholesterol-O-acyltransferase.

Summary A series of aryloxyalkylthioimidazoles have been synthesized and evaluated for their ability to interfere with the enzyme acyl-CoA (cholesterol- O -acyltransferase) (ACAT, EC 2.3.1.26). Most of the molecules possessed a good in vitro ACAT inhibitory activity with IC 50 values ranging between 0.1 and 2.0 μM. Some of them, eg , 2-5-[(4-isobutoxycarbonyl)phenoxy]-pentylthio-4,5-diphenylimidazole 13 , 2-3-[(4-isobutoxycarbonyl)phenoxy]-2-oximinopropylthio-4,5-diphenylimidazole 21 , 2-3-[(4-isobutoxycarbonyl)phenoxy]-2-hydrazonecarboxamidepropylthio-4.5-diphenylimidazole 26 , 2-[5-(2-pyridoxy)-pentylthio]-4,5-diphenylimidazole 40 and 2-5-[(3,5-diterbutyl-4-hydroxy)phenylthio]pentylthio-4,5-diphenylimidazole 42 , were more potent (range of activity 10–90 nM). They were also more potent with respect to the reference CI-976. When administered orally in hyperlipemic rats, at 10 and 50 mg/kg doses, some representative compounds, like 2-3-[(4-isobutoxycarbonyl)phenoxy]-2-hydroxypropylthio-4, 5-diphenylimidazole 1, 13 and 26 , reduced VLDL/LDL-associated cholesterol levels by 30–50% and increased HDL cholesterol levels by 15–50%. In addition, liver accumulation of esterified cholesterol was counteracted (50–80% reduction) and liver ACAT ex vivo activity was decreased by 70–85%. Finally, the good efficacy displayed in an endogenous model of hypertriglyceridemia strongly supports the hypothesis of a good systemic availability, which constitutes one of the principal properties of a valuable ACAT inhibitor.