Orally Bioavailable SARS-CoV-2 Protease Inhibitors Bearing a Hydroxymethyl Ketone Warhead

The use of covalent warheads targeting the catalytic cysteine has been a cornerstone in the coronavirus main protease (M^pro) inhibitor development. Various electrophilic motifs have been explored, including aldehydes, nitriles, ketoamides, and hydroxymethyl ketones (HMKs). Recent efforts have mostly centered around nitrile warheads, given the success of Nirmatrelvir in the clinic. However, it is essential to identify and develop alternative chemotypes with distinct chemical and pharmacological profiles to prepare for future pandemics. Among such alternatives, HMKs are of particular interest because they balance reduced intrinsic electrophilicity with an excellent selectivity profile. Nevertheless, early HMK-based compounds, such as the clinical-stage M^pro inhibitor PF-00835231, suffered from poor oral bioavailability and therefore required intravenous administration, with or without prodrug derivatization of the hydroxyl group. In this work, we describe our efforts to advance the HMK field by discovering mCMX110, a lead compound that exhibits superior potency, increased unbound exposure in vivo, and favorable oral bioavailability in preclinical studies.