Peptidylarginine Deiminase (PAD) Inhibitor Optimization through Displacement of a Trapped Water Molecule

Excess protein citrullination, a post-translational modification converting arginine to citrulline, has been associated with a range of autoimmune and neurological disorders, as well as cancers. Protein citrullination is mediated by the peptidylarginine deiminase enzyme family (PAD1-4), and inhibition of one or several PAD isozymes in combination may offer a therapeutic approach to targeting these diseases. Building upon the discovery of PAD-PF2, an allosteric inhibitor of PAD1-4, herein, we report on the optimization of potency and pharmacokinetic properties while minimizing hERG channel liabilities within this novel chemical series. Through structure-based ligand design, a structural water was successfully displaced, allowing expansion of the ligand binding site and access to a previously unexplored hydrophobic pocket resulting in a 10-fold improvement in potency. Compound 4f demonstrated potent inhibition of PAD-mediated citrullination in human and rat neutrophils, reduced hERG channel liabilities, and good oral bioavailability in preclinical animal species.