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

Synthesis, reactions, and biological activity of 4,5-diarylimidazole-2-thiones (Review)

“…When the bromide 27 was treated with chloromercury 4,5-diphenylimidazole-2-thiolate, 4,5-diphenyl-1-(tetra-O-acetyl-β-D-glucopyranosyl)-4-imidazoline-2-thione (29) was formed [30]. 4,5-Diphenylimidazoles 32 and 33 were prepared as cholesterol acyltransferase inhibitors by the reaction of thione 1 with p-(2,3-epoxypropoxy)benzoic acid or its isobutyl ester, respectively, in ethanol [32,33] (35) in 42% yield, which showed inhibitory activity on human cytosolic phospholipase A2 [34]. The potassium salt of imidazolethione 1 reacted with 3-chloro-2,4-pentanedione to give the S-alkyl derivative 43 [42].…”

Novel Indoline-Based Acyl-CoA:Cholesterol Acyltransferase Inhibitor with Antiperoxidative Activity: Improvement of Physicochemical Properties and Biological Activities by Introduction of Carboxylic Acid

“…In atherosclerotic plaque, denaturized low-density lipoprotein (LDL), such as oxidized LDL, is taken up by macrophages and cholesterol is accumulated via esterification by ACAT. There have been some attempts to improve bioavailability of ACAT inhibitors by reduction of lipophilicity; – however, no bioavailable ACAT inhibitors have been successfully developed. It is very difficult to reduce the lipophilicity of ACAT inhibitors while maintaining their activities, because lipophilicity is the preferred property for the inhibition of esterification between two lipophilic substrate molecules (cholesterol and long chain fatty acid) by membrane-bound enzymes such as ACAT. , Furthermore, ACAT has two isozymes: ACAT-1 expressed in macrophages and adrenal glands, and ACAT-2 expressed in the intestine and liver. – Thus, adrenotoxicity is a critical problem for systemic bioavailable ACAT inhibitors, which may inhibit adrenal as well as macrophage ACAT.…”