Design, synthesis and pharmacology of aortic-selective acyl-CoA: Cholesterol O-acyltransferase (ACAT/SOAT) inhibitors

Discovery of Clinical Candidate 2-(4-(2-((1H-Benzo[d]imidazol-2-yl)thio)ethyl)piperazin-1-yl)-N-(6-methyl-2,4-bis(methylthio)pyridin-3-yl)acetamide Hydrochloride [K-604], an Aqueous-Soluble Acyl-CoA:Cholesterol O-Acyltransferase-1 Inhibitor

“…The J774 macrophage cell-culture assay was performed to assess the inhibition of the target cells by systemic antiatherosclerotic agents . ACAT inhibition by all the prepared compounds is described herein and compared with that of our previously reported compound, 1 , as an improvement index. The relationships between ACAT inhibition (IC 50 ) and the linker structure are summarized in Table .…”

“…As shown in Figure , introduction of the N , N -dimethylamino group into molecules such as 1-(2,6-diisopropylphenyl)-3-((1-(4-(dimethylamino)­benzyl)­cyclopentyl)­methyl)­urea (PD-132301) and 1,1′-(1,3-phenylenebis­(methylene))­bis­(1-cycloheptyl-3-(4-(dimethylamino)­phenyl)­urea) dihydrochloride (YM-17E) has been very effective at increasing aqueous solubility in acidic media. A comparison of compounds 66 and 67 shows that the N , N -dimethylaminomethyl group doubles the aqueous solubility (from 0.18 to 0.4 mg/mL) by increasing the basicity but dramatically decreases ACAT inhibition in J774 cells. As reported previously, the polar-ionic interaction around the binding site not only negatively affected the adaptability of the ligand-binding pocket or cleft in our head-to-tail design but also potentially obstructed the molecular permeability of the J774 cell membrane.…”

“…The N -alkylation reaction between 3-(1,4-diazepan-1-yl)­propan-1-ol ( 34 ) and 2-bromo- N -(2,6-diisopropylphenyl)­acetamide ( 35 ) provided anilide 36 , which was converted to mesylate 37 under the reaction conditions described above. The desired thioether, 38 , was obtained by reacting 37 with 5 in the conventional manner described above.…”

“…The researchers also demonstrated that ACAT-1 inhibitors can complement current therapies, such as immune-checkpoint blockade, by acting via a different mechanism. These fascinating trends prompted us to report our discovery of the clinical candidate 2-(4-(2-((1 H -benzo­[ d ]­imidazol-2-yl)­thio)­ethyl)­piperazin-1-yl)- N -(6-methyl-2,4-bis­(methylthio)­pyridin-3-yl)­acetamide hydrochloride ( 2 , K-604), − an aqueous-soluble ACAT-1 inhibitor developed from our lead compound, 9-(benzo­[ d ]­oxazol-2-ylthio)- N -(2,6-diisopropylphenyl)­nonanamide ( 1 ), as shown in Figure .…”

SOAT1 methylation is associated with coronary heart disease

“…SOAT1 is an important protein for regulating cholesterol absorption and it plays a pivotal role in the development of atherosclerosis. Recent studies have shown that the deletion of the SOAT1 gene in macrophages results in an increase in atherosclerotic lesion area in the aortas of hypercholesterolemia mice [28, 29]. In 1996, the production of genetically engineered mice lacking functional SOAT1 was first reported by Farese et al [30].…”