Leritrelvir (RAY1216) is a potent orally active inhibitor of the SARS-CoV-2 main protease, exhibiting a slow-tight binding mechanism with an inhibition constant (Ki) of 8.6 nM [1].

Leritrelvir (RAY1216) exhibits a drug-target residence time of 104 minutes [1]. It covalently attaches to the catalytic Cys145 via an α-ketoamide warhead [1]. Furthermore, Leritrelvir demonstrates antiviral activity against both the wild-type ancestral strains and variants of SARS-CoV-2 at concentrations ranging from 0-1000 nM over 72 hours [1].

Leritrelvir (RAY1216), administered intragastrically (i.g.) at doses ranging from 150-600 mg/kg/day for 5 days, effectively prolonged survival in mice infected with SARS-CoV-2 [1]. Pharmacokinetic parameters of Leritrelvir across various animal species were charted, indicating drug exposure and metabolism rates. In mice, following an intravenous (IV) dose of 3.0 mg/kg, an area under the curve (AUC(0-last)) of 7789 nM•h was recorded without available data for peak concentration (C_max) and time to reach this concentration (T_max). Conversely, an oral dose (PO) of 10 mg/kg yielded a C_max of 1287 nM, T_max of 2.0 hours, and an AUC(0-last) of 5698 nM•h with an elimination half-life (T_1/2) of 2.6 hours and an oral bioavailability (F%) of 22. In rats, the AUC(0-last) for an IV dose of 2.0 mg/kg was 4505 nM•h, while a PO dose of 10 mg/kg led to a C_max of 916 nM, T_max of 0.9 hours, an AUC(0-last) of 7429 nM•h, T_1/2 of 4.3 hours, and an F% of 33. In cynomolgus macaques, an IV dose of 1.0 mg/kg resulted in an AUC(0-last) of 1157 nM•h, whereas a PO dose of 5.0 mg/kg reached a C_max of 102 nM, T_max of 1.5 hours, an AUC(0-last) of 458 nM•h, T_1/2 of 14.9 hours, and F% of 8. These values denote the maximum concentration (C_max), time to C_max (T_max), total drug exposure (AUC), plasma clearance (Cl), steady-state volume of distribution (Vd_ss), half-life (T_1/2), and the percentage of oral bioavailability (F%) for Leritrelvir in each respective species [1].