Invention of MK-7845, a SARS-CoV‑2 3CL Protease Inhibitor Employing a Novel Difluorinated Glutamine Mimic

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 prote...

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Bibliographic Details
Published in:Journal of medicinal chemistry 2024-03, Vol.67 (5), p.3935-3958
Main Authors: Shurtleff, Valerie W., Layton, Mark E., Parish, Craig A., Perkins, James J., Schreier, John D., Wang, Yunyi, Adam, Gregory C., Alvarez, Nadine, Bahmanjah, Soheila, Bahnck-Teets, Carolyn M., Boyce, Christopher W., Burlein, Christine, Cabalu, Tamara D., Campbell, Brian T., Carroll, Steven S., Chang, Wonsuk, de Lera Ruiz, Manuel, Dolgov, Enriko, Fay, John F., Fox, Nicholas G., Goh, Shih Lin, Hartingh, Timothy J., Hurzy, Danielle M., Kelly, Michael J., Klein, Daniel J., Klingler, Franca-Maria, Krishnamurthy, Harini, Kudalkar, Shalley, Mayhood, Todd W., McKenna, Philip M., Murray, Edward M., Nahas, Debbie, Nawrat, Christopher C., Park, Steven, Qian, Dongming, Roecker, Anthony J., Sharma, Vijeta, Shipe, William D., Su, Jing, Taggart, Robert V., Truong, Quang, Wu, Yin, Zhou, Xiaoyan, Zhuang, Ningning, Perlin, David S., Olsen, David B., Howe, John A., McCauley, John A.
Format: Article
Language:English
Subjects:
Amides
Antiviral Agents - chemistry
Antiviral Agents - pharmacology
COVID-19
Cysteine Endopeptidases - chemistry
Glutamine - chemistry
Humans
Inventions
Protease Inhibitors - pharmacology
SARS-CoV-2
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Summary: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.
ISSN:0022-2623
1520-4804
1520-4804
DOI:10.1021/acs.jmedchem.3c02248