Although vinyl sulfones have been used as covalent warheads for inhibition of a wide range of cysteine proteases , there are relatively few reports of their use in vivo . To explore the potential of 1 as a drug lead for treatment or prevention of alphavirus infections, pharmacokinetic experiments were performed in mice following a 10 mg/kg i.v. dose (Figure ). Unfortunately, b-amidomethyl-vinyl sulfone 1 had very rapid clearance with plasma levels falling below the limit of MS detection after 1h. From the observable data points the plasma half-life was calculated as only ~10 min. As a control, the pharmacokinetics of the cyclic dihydropyrazolo pyrazin-4(5H)-one 2 were also determined (Figure ). In comparison to 1, the cyclic pyrazole 2 showed reduced plasma clearance with an i.v. half-life ~30 min and a 4-fold greater calculated plasma exposure. The rapid clearance of 1 compared to 2 suggested that the covalent b-amidomethyl-vinyl warhead was a liability for in vivo exposure in mice. Conversely, the improved exposure and reduced clearance of the dihydropyrazolo pyrazin-4(5H)-one 2 raised the question of whether it might function as a prodrug for the reactive b-amidomethylvinyl sulfone 1 if the aza-Michael reaction was reversible.