Discovery of preclinical candidate CG-0988, a novel severe acute respiratory syndrome coronavirus 2 3CL protease inhibitor bearing spirooxindole.

Although coronavirus disease (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is no longer a major global pandemic, the disease is still present and may progress into severe respiratory syndrome for many elder or immunocompromised individuals. The treatment options are very limited, and therefore improved therapies for COVID-19 are still needed. Herein, we described a novel class of covalent SARS-CoV-2 3C-like protease (3CLpro) inhibitors bearing a spirooxindole moiety. By minimizing the peptidomimetic properties of the original structure, we obtained a series of compounds exhibiting excellent potency and high metabolic stability in liver microsomes. This work culminated in the discovery of preclinical candidate CG-0988, which demonstrates excellent antiviral activity (EC50 = 4.0 nM against Omicron EG.5.1). Pharmacokinetic (PK) study of CG-0988 in rats and dogs exhibited favorable PK profiles, with oral availability of 59.2% (in rats) and 94.0% (in dogs), respectively. These findings indicate that CG-0988 is a promising 3CLpro inhibitor for oral administration, potentially without the need for a PK boosting agent.