Design, Synthesis, and Evaluation of Novel Prodrugs of Transition State Inhibitors of Norovirus 3CL Protease

Ester and carbamate prodrugs of aldehyde
bisulfite adduct inhibitors were synthesized in order to improve their
pharmacokinetic and pharmacodynamic properties. The inhibitory activity
of the compounds against norovirus 3C-like protease in enzyme and
cell-based assays was determined. The ester and carbamate prodrugs
displayed equivalent potency to those of the precursor aldehyde bisulfite
adducts and precursor aldehydes. Furthermore, the rate of ester cleavage
was found to be dependent on alkyl chain length. The generated prodrugs
exhibited low cytotoxicity and satisfactory liver microsomes stability
and plasma protein binding. The methodology described herein has wide
applicability and can be extended to the bisulfite adducts of common
warheads employed in the design of transition state inhibitors of
serine and cysteine proteases of medical relevance.