Another design to replace the 4-methoxy indole was the (2R)-tetrahydrofuran-2-carboxylate, which molecular modeling suggested could make additional favorable protein interactions with a Gln189 side chain and led to the preparation of 3. Initially, this derivative appeared to display reversible binding kinetics. However, further kinetic studies of compound 3 with the SARS CoV-1 3CLpro protein demonstrated irreversible time-dependent inactivation of this enzyme (kobs/I = 5834 ± 151 M–1 s–1). Additionally, 3 possessed potent antiviral activity in Vero cells (EC50 = 2.4 μM) and solubility in vehicle formulations almost 20-fold higher than 22. Evaluation of the pharmacokinetic profile of 3 in rat suggested that this inhibitor possessed properties potentially sufficient for an IV continuous infusion dosing paradigm.42