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

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

  • J Med Chem. 2024 Feb 16. doi: 10.1021/acs.jmedchem.3c02248.
Valerie W Shurtleff 1,  Mark E Layton 1,  Craig A Parish 2,  James J Perkins 1,  John D Schreier 1,  Yunyi Wang 1,  Gregory C Adam 1,  Nadine Alvarez 3,  Soheila Bahmanjah 2,  Carolyn M Bahnck-Teets 1,  Christopher W Boyce 1,  Christine Burlein 1,  Tamara D Cabalu 1,  Brian T Campbell 1,  Steven S Carroll 1,  Wonsuk Chang 2,  Manuel de Lera Ruiz 1,  Enriko Dolgov 3,  John F Fay 1,  Nicholas G Fox 2,  Shih Lin Goh 1,  Timothy J Hartingh 1,  Danielle M Hurzy 1,  Michael J Kelly 3rd 1,  Daniel J Klein 1,  Franca-Maria Klingler 4,  Harini Krishnamurthy 1,  Shalley Kudalkar 1,  Todd W Mayhood 2,  Philip M McKenna 1,  Edward M Murray 1,  Debbie Nahas 1,  Christopher C Nawrat 1,  Steven Park 3,  Dongming Qian 5,  Anthony J Roecker 1,  Vijeta Sharma 3,  William D Shipe 1,  Jing Su 2,  Robert V Taggart 1,  Quang Truong 2,  Yin Wu 5,  Xiaoyan Zhou 2,  Ningning Zhuang 5,  David S Perlin 3,  David B Olsen 1,  John A Howe 1,  John A McCauley 1
Affiliations

Affiliations

  • 1 Merck & Co., Inc., West Point, Pennsylvania 19486, United States.
  • 2 Merck & Co., Inc., Rahway, New Jersey 07065, United States.
  • 3 Center for Discovery and Innovation, Hackensack Meridian Health, Nutley, New Jersey 07110, United States.
  • 4 MSD (U.K.) Limited, London EC2M 6UR, U.K.
  • 5 Viva Biotech Ltd., Shanghai 201318, China.
PMID: 38365209 DOI: 10.1021/acs.jmedchem.3c02248
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.

Figures
Products
  • Cat. No.
    Product Name
    Description
    Target
    Research Area
  • HY-157778
    SARS-CoV-2 3CL Protease Inhibitor