Novel aryloxyalkylthioimidazoles as inhibitors of acyl-CoA: Cholesterol-O-acyltransferase

Article abstract of DOI:10.1016/0223-5234(96)88207-9

A series of aryloxyalkcylthioimidazoles 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 IC₅₀ 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-oximopropylthio} -4,5-diphenylimidazole 21, 2-{3-[(4-isobutoxycarbonyl)phenoxy]-2-hydrazonecarboxamidepropylthio}-4,5 -diphenylimidazole 26, 2-[5-(2-pyridoxy)-pentylthio]-4,5-dipilenylimidazole 40 and 2-{5-[(3,5-diterbutyl-4-hydroxy)phenylthiolpentylthio}-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.