학술논문
Invention of MK-7845, a SARS-CoV-2 3CL Protease Inhibitor Employing a Novel Difluorinated Glutamine Mimic
Document Type
Article
Author
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.
Source
Journal of Medicinal Chemistry; March 2024, Vol. 67 Issue: 5 p3935-3958, 24p
Subject
Language
ISSN
00222623; 15204804
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.