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(1H,3H)-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 EGT710. EGT710 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.