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.

中文翻译：

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2-（4-（2-（（（1H-苯并[d]咪唑-2-基）硫代）乙基）哌嗪-1-基）-N-（6-甲基-2，-）的四种代谢物的合成和药代动力学评估4-双-（甲硫基）吡啶-3-基）乙酰胺盐酸盐[K-604]，一种酰基辅酶A：胆固醇O-酰基转移酶-1抑制剂。

我们合成并鉴定了酰基辅酶A：胆固醇O-酰基转移酶（ACAT）-1抑制剂K-604的四种代谢物（1）。使用过氧化氢和钨酸钠与磷酸或三氟乙醇作为溶剂控制区域选择性的混合试剂，由1制备代谢物M1和M2中的两种。在-78°C下将4b暴露于次氯酸叔丁酯后，单磺氧化反应以优异的产率提供了M3的合成中间体。建立了M4的有效合成方法。体外代谢研究显示，使用人肝微粒体的清除率很高（720μL/ min / mg蛋白）为1。我们给猴子口服10 mg / kg的单剂1，因为其体外代谢模式非常相似。幸运的是，药物浓度1比M1，M2，