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Discovery of novel bicyclic[3.3.0]proline peptidyl α-ketoamides as potent 3CL-protease inhibitors for SARS-CoV-2.

ABSTRACT: The outbreak of SARS-CoV-2 has caused global crisis on health and economics. The multiple drug-drug interaction risk associated with ritonavir warrants specialized assessment before using Paxlovid. Here we report a multiple-round SAR study to provide a novel bicyclic[3.3.0]proline peptidyl α-ketoamide compound 4a, which is endowed with excellent antiviral activities and pharmacokinetic properties. Also, in vivo HCoV-OC43 neonatal mice model demonstrated compound 4a has good in vivo efficacy. Based on these properties, compound 4a worth further SAR optimization with the goal to develop compounds with better pharmacokinetic properties and finally to realize single agent efficacy in human.

SUBMITTER: Chen X

PROVIDER: S-EPMC10176891 | biostudies-literature | 2023 Jun

REPOSITORIES: biostudies-literature

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Discovery of novel bicyclic[3.3.0]proline peptidyl α-ketoamides as potent 3CL-protease inhibitors for SARS-CoV-2.

Chen Xiaoxin X Li Peng P Huang Jianzhou J Yang Yaxun Y Zhang Haoyu H Wang Zheng Z Zhu Zhenzhen Z Wang Jingjing J Zhang Jianchen J Chen Kevin K He Haiying H Long Chaofeng C Chen Shuhui S

Bioorganic & medicinal chemistry letters 20230512

The outbreak of SARS-CoV-2 has caused global crisis on health and economics. The multiple drug-drug interaction risk associated with ritonavir warrants specialized assessment before using Paxlovid. Here we report a multiple-round SAR study to provide a novel bicyclic[3.3.0]proline peptidyl α-ketoamide compound 4a, which is endowed with excellent antiviral activities and pharmacokinetic properties. Also, in vivo HCoV-OC43 neonatal mice model demonstrated compound 4a has good in vivo efficacy. Bas ...[more]

PMID: 37182612

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