Synthesis and characterization of Keap1 prodrug inhibitors: a promising approach against NASH.

Inhibiting the protein-protein interaction between Keap1 and Nrf2 is a promising strategy in order to overcome oxidative stress and the many diseases that it can provoke. Particularly we will focus on small molecules that could improve treatment against non-alcoholic steatohepatitis (NASH), a progressive disease caused by excessive accumulation of fat in the liver not associated with alcohol consumption. At present, the best compounds that have been proven to bind to the target Keap1 are all characterized by carboxylic acid moiety. This leads to poor membrane permeability, metabolic stability and general non optimal pharmacokinetic properties. Therefore, in this project we aim to mask this group by using two different prodrug strategies: methyl ester prodrugs and thiazolidinone prodrugs. Eight different prodrugs were obtained, and the most promising one (UCAB#1299, a thiazolidinone prodrug of lead compound UCAB#1182) was tested for stability in H2O2 using liquid chromatography-mass spectrometry (LCMS) system, proving to be successfully cleaved by ROS species. Methyl ester prodrugs instead have shown poor solubility, despite a suitable value of cLogD under 5. Overall, the prodrug strategy seems to be the most promising one to enhance pharmacokinetic properties of active compounds, and it could therefore open the way for the synthesis of better inhibitors of this PPI interaction.