Author: Badir, Shorouk O. ; Kowalski, Jason R. ; Deprez, Nicholas R. ; Xu, Jing ; McCabe Dunn, Jamie M. ; Gauthier, Donald R. Jr. ; Qi, Ji ; Padivitage, Nilusha ; Andreani, Teresa ; Peng, Feng ; Bade, Rachel S. ; Cohen, Ryan D. ; Confer, Alex M. ; Dal Poggetto, Guilherme ; Kwok, Thomas Tai-min ; Castro, Steve ; Sakhaei, Zeinab ; Salehi Marzijarani, Nastaran ; Liu, Yong ; Wolstenholme, Charles ; Lin, Mingxiang ; Kassim, Brittany ; Schenk, David J. ; Hughes, Jonathan M. E. ; Welch, Cody ; Hartmanshenn, Clara ; Popov, Stasik ; Brunskill, Andrew P. J. ; Drout, Riki

We describe the rapid end-game process development for the first good manufacturing process (GMP) delivery of the 3C-like protease inhibitor MK-7845 (1), an exptl. treatment for SARS-CoV-2.Three operations, including an amide-coupling, oxidation, and crystallization, were rapidly developed and implemented on a kilogram scale to enable critical safety studies and phase 1 clin. trials to move forward on a highly accelerated timeline.Key to the success of this undertaking was our focus on purging key impurities formed in the amide-coupling step, identifying a safe and scalable TEMPO/NaOCl oxidation to access 1, and developing an active pharmacutical ingredient (API) crystallization that addressed challenges associated with gumming, oiling, and agglomeration.Notably, this delivery was completed within an approx. six-week time frame, and challenges associated with this highly accelerated delivery are also discussed.

14 Mar 2024·Journal of Medicinal ChemistryQ1 · MEDICINE

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

Q1 · MEDICINE

Article

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

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.

Viruses

Novel Pan-Coronavirus 3CL Protease Inhibitor MK-7845: Biological and Pharmacological Profiling

Article

Author: Nelson, Andrew M ; Dolgov, Enriko ; Zhou, Xiaoyan ; Mayhood, Todd W ; Shurtleff, Valerie W ; Cabalu, Tamara D ; Nizar, Fatima ; Smith, Keith ; Boyce, Christopher W ; McCauley, John A ; Alvarez, Nadine ; Layton, Mark E ; Salhab, Imad ; Howe, John A ; Olsen, David B ; Iwamoto, Daniel V ; Getty, Krista L ; Adam, Gregory C ; Fox, Nicholas G ; Sahay, Khushboo ; Bahnck-Teets, Carolyn M ; Lin Goh, Shih ; Sharma, Vijeta ; Rasheed, Risha ; Fay, John F ; Perlin, David S ; Parish, Craig A ; Murgolo, Nicholas ; Burlein, Christine ; Zimmerman, Matthew D ; Park, Steven

Severe acute respiratory syndrome coronavirus type 2 (SARS-CoV-2) continues to be a global threat due to its ability to evolve and generate new subvariants, leading to new waves of infection. Additionally, other coronaviruses like Middle East respiratory syndrome coronavirus (MERS-CoV, formerly known as hCoV-EMC), which first emerged in 2012, persist and continue to present a threat of severe illness to humans. The continued identification of novel coronaviruses, coupled with the potential for genetic recombination between different strains, raises the possibility of new coronavirus clades of global concern emerging. As a result, there is a pressing need for pan-CoV therapeutic drugs and vaccines. After the extensive optimization of an HCV protease inhibitor screening hit, a novel 3CLPro inhibitor (MK-7845) was discovered and subsequently profiled. MK-7845 exhibited nanomolar in vitro potency with broad spectrum activity against a panel of clinical SARS-CoV-2 subvariants and MERS-CoV. Furthermore, when administered orally, MK-7845 demonstrated a notable reduction in viral burdens by >6 log orders in the lungs of transgenic mice infected with SARS-CoV-2 (K18-hACE2 mice) and MERS-CoV (K18-hDDP4 mice).

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Indication	Highest Phase	Country/Location	Organization	Date
Coronavirus Infections	Preclinical	United States	Merck & Co., Inc.	16 Feb 2024

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