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 (t1/2) by reducing metabolic clearance and increasing
volume of distribution (Vss). Our efforts culminated
in the identification of a biaryl series, with an expected longer t1/2 in human than UCB7362 while
maintaining a similar in vitro off-target hit rate.