Syntheses and pharmacokinetic evaluations of four metabolites of 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 acyl-CoA:cholesterol O-acyltransferase-1 inhibitor

• Published in: Bioorganic & medicinal chemistry 2020-06, Vol.28 (11), p.115457, Article 115457
• Main Authors: Shibuya, Kimiyuki, Miura, Toru, Ohgiya, Tadaaki, Omichi, Kozo, Tsunenari, Yoshihiko
• Format: Article
• Language: English
• Subjects: ACAT-1 inhibitor; Acyl-CoA:cholesterol O-acyltransferase; Clearance; CYP3A4; K-604; Metabolic pattern; Metabolite; Microsomes; Monosulfoxidation; Pharmacokinetics
• ISSN: 0968-0896; 1464-3391
• DOI: 10.1016/j.bmc.2020.115457

[Display omitted] We synthesized and identified four metabolites of acyl-coenzyme A:cholesterol O-acyltransferase (ACAT)-1 inhibitor, K-604 (1). Two of the metabolites M1 and M2, were prepared from 1 using a combination reagent of hydrogen peroxide and sodium tungstate with either phosphoric acid or trifluoroethanol as the solvent to control the regioselectivity. Upon exposure of 4b to tert-butyl hypochlorite at −78 °C, the monosulfoxidation afforded synthetic intermediate of M3 in excellent yield. The efficient synthesis of M4 was established. The in vitro metabolic study exhibited a high clearance value (720 μL/min/mg protein) of 1 using human liver microsomes. We orally administered a single dose of 10 mg/kg of 1 to monkeys because the in vitro metabolic patterns are quite similar. Fortunately, the drug concentration of 1 was much higher than those of M1, M2, M3 and M4.