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Effective, safe, and pharmacokinetically suitable drugs are urgently needed to curb the ongoing COVID-19 pandemic. The main protease or 3C-like protease (M^pro or 3CL^pro) of SARS-CoV-2 is considered an important target to formulate potent drugs corresponding to its crucial role in virus replication and maturation in addition to its relatively conserved active site. Promising baseline data on the potency and safety of drugs targeting SARS-CoV-2 M^pro are currently available. However, preclinical and clinical data on the pharmacokinetic profiles of these drugs are very limited. This review discusses the potency, safety, and pharmacokinetic profiles of potential inhibitors of SARS-CoV-2 M^pro and forward directions on the development of future studies focusing on COVID-19 therapeutics.