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
  • 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.

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