Bis[(para-methoxy)benzyl] Phosphonate Prodrugs with Improved Stability and Enhanced Cell Penetration

A series of substituted bis[(para-methoxy)benzyl] (bisPMB) esters of 1-naphthalenemethylphosphonate (NMPA) were synthesized and evaluated as phosphonate prodrugs. BisPMB NMPA esters (4b and 4c) with significantly improved aqueous stability were identified that also resulted in increased intracellular levels of NMPA following prodrug incubation with primary rat hepatocytes.