Discovery and Preclinical Profile of ALG-097558, a Pan-Coronavirus 3CLpro Inhibitor

The SARS-CoV-2 outbreak of 2019 had a devastating impact
on global
health and economies worldwide. The viral cysteine protease (3CLpro)
is responsible for viral polypeptide bond cleavages and is therefore
an essential target to inhibit viral replication. Here, we report
the discovery of an orally available, reversible covalent inhibitor
of the SARS-CoV-2 main protease that is also highly active across
other human coronaviruses and demonstrated oral efficacy in a Syrian
hamster infection model at low plasma concentrations. Projection of
pharmacokinetics (PK) in humans, based on PK studies in preclinical
species and enhanced in vitro/in vivo efficacy of ALG-097558 (7) indicated the potential for BID dosing without the need
for ritonavir, the PK boosting component of Paxlovid. After preclinical
safety and pharmacological studies, ALG-097558 has progressed to phase
1 clinical trials.