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

TY - JOUR

T1 - Invention of MK-7845, a SARS-CoV-2 3CL Protease Inhibitor Employing a Novel Difluorinated Glutamine Mimic

AU - Shurtleff, Valerie W.

AU - Layton, Mark E.

AU - Parish, Craig A.

AU - Perkins, James J.

AU - Schreier, John D.

AU - Wang, Yunyi

AU - Adam, Gregory C.

AU - Alvarez, Nadine

AU - Bahmanjah, Soheila

AU - Bahnck-Teets, Carolyn M.

AU - Boyce, Christopher W.

AU - Burlein, Christine

AU - Cabalu, Tamara D.

AU - Campbell, Brian T.

AU - Carroll, Steven S.

AU - Chang, Wonsuk

AU - de Lera Ruiz, Manuel

AU - Dolgov, Enriko

AU - Fay, John F.

AU - Fox, Nicholas G.

AU - Goh, Shih Lin

AU - Hartingh, Timothy J.

AU - Hurzy, Danielle M.

AU - Kelly, Michael J.

AU - Klein, Daniel J.

AU - Klingler, Franca Maria

AU - Krishnamurthy, Harini

AU - Kudalkar, Shalley

AU - Mayhood, Todd W.

AU - McKenna, Philip M.

AU - Murray, Edward M.

AU - Nahas, Debbie

AU - Nawrat, Christopher C.

AU - Park, Steven

AU - Qian, Dongming

AU - Roecker, Anthony J.

AU - Sharma, Vijeta

AU - Shipe, William D.

AU - Su, Jing

AU - Taggart, Robert V.

AU - Truong, Quang

AU - Wu, Yin

AU - Zhou, Xiaoyan

AU - Zhuang, Ningning

AU - Perlin, David S.

AU - Olsen, David B.

AU - Howe, John A.

AU - McCauley, John A.

N1 - Publisher Copyright: © 2024 American Chemical Society.

PY - 2024/3/14

Y1 - 2024/3/14

N2 - 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.

AB - 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.

UR - https://www.scopus.com/pages/publications/85186103264

U2 - 10.1021/acs.jmedchem.3c02248

DO - 10.1021/acs.jmedchem.3c02248

M3 - Article

C2 - 38365209

SN - 0022-2623

VL - 67

SP - 3935

EP - 3958

JO - Journal of medicinal chemistry

JF - Journal of medicinal chemistry

IS - 5

ER -