Protease inhibitor drugs with improved PK, bioavailability
While there are many successes in protease inhibitor drug development including antivirals, anti-cancer and others in preclinical stages, most developments have failed due to weak PK and oral bioavailability of the inhibitors. Improvement of PK and oral bioavailability of protease inhibitors is crucial for new drug development. The therapeutic potential of existing inhibitors, particularly aldehyde-based inhibitors, is severely compromised due to their low bioavailability and plasma stability.
As a first step towards circumventing this limitation, researchers at K-State and Wichita State have recently introduced the use of aldehyde-based adduct salts as a latent form of the aldehyde. These salts were then further modified to produce the series of ester and amino acid-derived carbamate prodrug variants, which demonstrated comparable pharmacological activity in vitro and in cell-based systems as the precursor aldehydes by reverting to the aldehyde at physiological pH. Following oral or parenteral administration and absorption into the bloodstream, the prodrug undergoes hydrolysis to yield the bisulfite adduct and subsequently releases the aldehyde. This innovation is potentially applicable to aldehyde inhibitors of any serine or cysteine protease, as well as α-ketoamides and α-ketoheterocycles. Thus, useful therapeutics can be potentially developed based on this approach.