Elshan, N. G. R. D.; Wolff, K. C.; Weiss, F.; Ghorai, S.; Grabovyi, G.; Wilson, K.; Riva, L.; Woods, A. K.; Pedroarena, J.; Nazarian, A.; Liu, Y.; Mazumdar, W.; Song, L.; Okwor, N.; Malvin, J.; Bakowski, M. A.; Kirkpatrick, M. G.; Gebara-Lamb, A.; Huang, E.; Nguyen-Tran, V. T. B.; Chi, V.; Li, S.; Lee, K.-J.; McNamara, C. W.; Gupta, A. K.; Rahimi, A.; Chen, J. J.; Joseph, S. B.; Schultz, P. G.; Chatterjee, A. K.

The use of covalent warheads targeting the catalytic cysteine has been a cornerstone in coronavirus main protease (Mpro) inhibitor development, where various electrophilic motifs have been used including aldehydes, nitriles, ketoamides, and hydroxymethyl ketones (HMKs). Recent efforts have been mostly centered around nitrile warheads, given the success of compounds like Nirmatrelvir and Ensitrelvir in the clinic. However, finding and advancing alternative chemotypes with differentiating chemical and pharmacological profiles is essential for future pandemic preparedness. Among such alternatives, HMKs hold special interest because they balance reduced intrinsic electrophilicity with an excellent selectivity profile. Nevertheless, early HMK-based compounds, such as the clinical stage Mpro inhibitor PF-00835231, suffered from poor oral bioavailability and therefore required intravenous administration, with or without prodrug derivatization of the hydroxyl group. Here, we describe our efforts in advancing the HMK field via the discovery of mCMX110, a lead that has superior potency, increased unbound exposure in vivo, and favorable oral bioavailability in preclinical studies.