Abstract：
Type II transmembrane serine proteases represent pharmacological targets for blocking entry and spread of influenza or coronaviruses. In this study, the depletion rates of the 3-amidinophenylalanine (3-APhA)-derived matriptase/TMPRSS2 inhibitors MI-463, MI-472, MI-485 or MI-1900 were determined by LC-MS/MS measurements over a period of 300 min using suspensions of rat, dog and cynomolgus monkey primary hepatocytes. From these in vitro pharmacokinetic (PK) experiments, intrinsic clearance values (Clint) were evaluated, and in vivo pharmacokinetic parameters (hepatic clearance, hepatic extraction ratio and bioavailability) were predicted. It was found that rat hepatocytes were the most active in the metabolism of 3-APhA derivatives (Clint 31.9-37.8 mL/min/kg), whereas dog and monkey cells displayed somewhat lower clearance of these compounds (Clint 6.6-26.7 mL/min/kg). These data support elucidation of important PK properties of anti-TMPRSS2/anti-matriptase 3-APhAs using mammalian hepatocyte models and thus contribute to the optimization of lead compounds.
摘要：
II型跨膜丝氨酸蛋白酶代表阻断流感或冠状病毒进入和传播的药理学靶标。在这项研究中,3-脒基苯丙氨酸（3-AphA）衍生的间质蛋白酶/TMPRSS2抑制剂MI-463，MI-472，MI-485或MI-1900的耗竭率通过LC-MS/MS测量在300分钟内使用大鼠悬浮液，狗和食蟹猴原代肝细胞。从这些体外药代动力学（PK）实验中，评估了固有间隙值(Clint)，和体内药代动力学参数(肝清除率，肝提取率和生物利用度）进行了预测。发现大鼠肝细胞在3-APhA衍生物的代谢中最活跃（克林特31.9-37.8mL/min/kg），而狗和猴细胞对这些化合物的清除率略低（Clint6.6-26.7mL/min/kg）。这些数据支持使用哺乳动物肝细胞模型阐明抗TMPRSS2/抗间质蛋白酶3-APhAs的重要PK特性，因此有助于优化先导化合物。
