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Discovery of CMX990: A Potent SARS-CoV-2 3CL Protease Inhibitor Bearing a Novel Covalent Warhead (preprint)
biorxiv; 2023.
Preprint
in English
| bioRxiv | ID: ppzbmed-10.1101.2023.10.24.563688
ABSTRACT
There remains a need to develop novel SARS-CoV-2 therapeutic options that improve upon existing therapies by increased robustness of response, fewer safety liabilities, and global-ready accessibility. Functionally critical viral main protease (Mpro, 3CLpro) of SARS-CoV-2 is an attractive target due to its homology within the coronaviral family, and lack thereof towards human proteases. In this disclosure, we outline the advent of a novel SARS-CoV-2 3CLpro inhibitor, CMX990, bearing an unprecedented trifluoromethoxymethyl ketone warhead. Compared with the marketed drug nirmatrelvir (combination with ritonavir = Paxlovid), CMX990 has distinctly differentiated potency (~5x more potent in primary cells) and human in vitro clearance (>4x better microsomal clearance and >10x better hepatocyte clearance), with good in vitro-in vivo correlation. Based on its compelling preclinical profile and projected once or twice a day dosing supporting unboosted oral therapy in humans, CMX990 advanced to a Phase 1 clinical trial as an oral drug candidate for SARS-CoV-2.
Full text:
Available
Collection:
Preprints
Database:
bioRxiv
Language:
English
Year:
2023
Document Type:
Preprint
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