Discovery of an Orally Bioavailable Reversible Covalent SARS-CoV‑2 Mpro Inhibitor with Pan-Coronavirus Activity

Resulting in several million deaths globally, the COVID-19 pandemic has highlighted the criticality of antiviral drugs during a viral pandemic. Herein, we describe our efforts toward targeting SARS-CoV-2 Mpro, a key viral protease, which led to the discovery of compound 18, a reversible covalent inhibitor with potent antiviral activity against several clinical variants of SARS-CoV-2. Compound 18 demonstrated dose-dependent efficacy in a mouse-adapted SARS-CoV-2 infection model, with favorable pharmacokinetic profiles in mice, rats, dogs, and monkeys.新型冠状病毒肺炎（COVID-19）全球大流行已造成全球数百万例死亡，凸显了病毒性大流行期间抗病毒药物的核心作用。本研究详述了我们针对严重急性呼吸综合征冠状病毒2型主蛋白酶（SARS-CoV-2 Mpro）——一种关键病毒蛋白酶——的研发工作，最终成功发现化合物18：一种可逆共价抑制剂，对多种临床流行的SARS-CoV-2变异株均展现出强效抗病毒活性。化合物18在小鼠适应性SARS-CoV-2感染模型中呈现出剂量依赖性的抗病毒疗效，同时在小鼠、大鼠、犬与猴体内均表现出良好的药代动力学特性。