Design of Novel Series of Antimalarial PMX Inhibitors with Increased Half-Life via Molecular Property Optimization

Plasmepsin X (PMX) has been identified as a multistage antimalarial target. PMX is a malarial aspartyl protease essential for merozoite egress from infected red blood cells and invasion of the host erythrocytes. Previously, we reported the identification of PMX inhibitors by structure-based optimization of a cyclic guanidine core. Preclinical assessment of UCB7362, which displayed both in vitro and in vivo antimalarial activity, revealed a suboptimal dose paradigm (once daily dosing of 50 mg for 7 days for treatment of uncomplicated malaria) relative to current standard of care (three-dose regime). We report here the efforts toward extending the half-life (t(1/2)) by reducing metabolic clearance and increasing volume of distribution (Vss). Our efforts culminated in the identification of a biaryl series, with an expected longer t(1/2) in human than UCB7362 while maintaining a similar in vitro off-target hit rate.