Structure-Based Design, Synthesis and Biological Evaluation of Peptidomimetic Aldehydes as a Novel Series of Antiviral Drug Candidates Targeting the SARS-CoV-2 Main Protease

Wenhao Dai; Bing Zhang; Xia-Ming Jiang; Haixia Su; Jian Li; Yao Zhao; Xiong Xie; Zhenming Jin; Jingjing Peng; Fengjiang Liu; Chunpu Li; You Li; Fang Bai; Haofeng Wang; Xi Cheng; Xiaobo Cen; Shulei Hu; Xiuna Yang; Jiang Wang; Xiang Liu; Gengfu Xiao; Hualiang Jiang; Zihe Rao; Leike Zhang; Yechun Xu; Haitao Yang; Hong Liu

The copyright holder for this preprint (which was not peer-reviewed) is the . https://doi.org/10.1101/2020.03.25.996348 doi: bioRxiv preprint ng/mL), and a good bioavailability of 87.8%. Metabolic stability of 13a in mice was also good (CL = 17.4 mL/min/mg). When administered intraperitoneal (20mg/kg), subcutaneous (5mg/kg) and intravenous (5mg/kg), compound 11b also showed good PK properties. Considering the danger of COVID-19, we selected the intravenous drip administration to further study. Compared with 11a administrated via intravenous, the half-life (1.65h) of 11b is shorter and the clearance rate is faster (CL = 20.6 mL/min/mg). Compound 11a was selected for further investigation with intravenous drip dosing on rats and dogs. The results showed ( Table S3 ) that 11a exhibited long T 1/2 (rat, 7.6 h and dog, 5.5h), low clearance rate (rat, 4.01 mL/min/kg and dogs, 5.8 mL/min/kg) and high AUC value (rat, 41500 h*ng/mL and dog, 14900 h*ng/mL)).