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J Med Chem ; 67(5): 3935-3958, 2024 Mar 14.
Article in English | MEDLINE | ID: mdl-38365209

ABSTRACT

As SARS-CoV-2 continues to circulate, antiviral treatments are needed to complement vaccines. The virus's main protease, 3CLPro, is an attractive drug target in part because it recognizes a unique cleavage site, which features a glutamine residue at the P1 position and is not utilized by human proteases. Herein, we report the invention of MK-7845, a novel reversible covalent 3CLPro inhibitor. While most covalent inhibitors of SARS-CoV-2 3CLPro reported to date contain an amide as a Gln mimic at P1, MK-7845 bears a difluorobutyl substituent at this position. SAR analysis and X-ray crystallographic studies indicate that this group interacts with His163, the same residue that forms a hydrogen bond with the amide substituents typically found at P1. In addition to promising in vivo efficacy and an acceptable projected human dose with unboosted pharmacokinetics, MK-7845 exhibits favorable properties for both solubility and absorption that may be attributable to the unusual difluorobutyl substituent.


Subject(s)
COVID-19 , Glutamine , Humans , Glutamine/chemistry , SARS-CoV-2 , Cysteine Endopeptidases/chemistry , Inventions , Protease Inhibitors/pharmacology , Amides , Antiviral Agents/pharmacology , Antiviral Agents/chemistry
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