Invention of MK-7845, a SARS-CoV-2 3CL Protease Inhibitor Employing a Novel Difluorinated Glutamine Mimic.
Valerie W ShurtleffMark E LaytonCraig A ParishJames J PerkinsJohn D SchreierYunyi WangGregory C AdamNadine AlvarezSoheila BahmanjahCarolyn M Bahnck-TeetsChristopher W BoyceChristine BurleinTamara D CabaluBrian T CampbellSteven S CarrollWonsuk ChangManuel de Lera RuizEnriko DolgovJohn F FayNicholas G FoxShih Lin GohTimothy J HartinghDanielle M HurzyMichael J KellyDaniel J KleinFranca-Maria KlinglerHarini KrishnamurthyShalley KudalkarTodd W MayhoodPhilip M McKennaEdward M MurrayDebbie NahasChristopher C NawratSteven ParkDongming QianAnthony J RoeckerVijeta SharmaWilliam D ShipeJing SuRobert V TaggartQuang TruongYin WuXiaoyan ZhouNingning ZhuangDavid S PerlinDavid B OlsenJohn A HoweJohn A McCauleyPublished in: Journal of medicinal chemistry (2024)
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.