Discovery of EGT710, an Oral Nonpeptidomimetic Reversible Covalent SARS-CoV-2 Main Protease Inhibitor

The coronavirus main protease (3CL^pro, M^pro, nsp5) is a highly conserved cysteine protease unique to the Coronaviridae family, including SARS-CoV-2, and is a validated target for the treatment of COVID-19. Our efforts focused on the identification of a nonpeptidomimetic M^pro inhibitor, due to the potential for superior pharmacological properties. Herein, we report our efforts leveraging virtual screening and X-ray crystallography that enabled a structure-based drug design approach, leading to the discovery of series of quinazoline-2,4(1<i>H</i>,3<i>H</i>)-dione and oxoimidazolidine-4-carbonitrile compounds with potent inhibition of SARS-CoV-2 M^pro as well as other coronaviruses main proteases. Extensive lead optimization focusing on pharmacokinetic properties, developability, and breadth of activity across coronaviruses, led to the identification of <b>EGT710</b>. <b>EGT710</b> demonstrates excellent potency against SARS-CoV-2 infection in a primary differentiated normal human bronchial epithelial (dNHBE) cellular assay, as well as a favorable pharmacology profile that supported advancement into preclinical and clinical studies.