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

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.

Progress in Research on Inhibitors Targeting SARS-CoV-2 Main Protease (Mpro)

“…Most SARS-CoV-2 M pro covalent inhibitors reported contain amides as Gln mimics at P1. To develop a new inhibitor, Shurtleff’s team chose difluorobutyl as a substituent at this position, obtaining the compound MK-7845 (Figure C). MK-7845 was highly potent in vitro (IC 50 = 8.7 nM in WT) and showed potent efficacy in an in vivo viral infection model.…”

Rapid End-Game Process Development and First GMP Production of MK-7845: An Experimental Antiviral Treatment for COVID-19

“…The discovery route end game to access 1 is shown in Scheme and features a HATU-mediated coupling of acid 2 with amine S -3 to afford the penultimate intermediate S -4 . This was followed by a Dess-Martin Periodinane (DMP) oxidation and chromatographic purification to afford MK-7845 ( 1 ).…”

“…The urgent need for treatment and prevention led to the rapid development of ground-breaking vaccines as well as two mechanistically different antiviral treatments. , These antivirals included the nucleoside polymerase inhibitor, molnupiravir (MK-4482, formerly EIDD-2801), developed by Merck & Co., Inc., Rahway, NJ, USA, and Ridgeback Biotherapeutics, − and the 3C-like protease inhibitor nirmatrelvir, a component of Paxlovid, developed by Pfizer (Figure ). As part of our efforts to address the evolving needs of patients infected with SARS-CoV-2, we developed another experimental 3C-like protease inhibitor, MK-7845 ( 1 ). − This paper describes the development of a scalable end game consisting of an amide coupling between acid 2 and amine 3 , subsequent alcohol oxidation, and active pharmacutical ingredient (API) crystallization for the first good manufacturing process (GMP) production of MK-7845 ( 1 ) (Scheme ).…”

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

“…Recently, a novel reversible covalent protease inhibitor from the ketoamide class, MK-7845, has been identified. The compound incorporates a unique P1 difluoroalkyl group replacing the γ-lactam present in most covalent 3CLPro inhibitors reported to date [12]. MK-7845 exhibits favorable pharmacokinetics without boosting and physicochemical properties that provide good oral bioavailability with improved antiviral activity.…”