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?:abstract
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Monophosphate prodrug analogs of 2\'-deoxy-2\'-fluoro-2\'-C-methylguanosine have been reported as potent inhibitors of hepatitis C virus (HCV) RNA-dependent RNA polymerase. These prodrugs also display potent anti-dengue activities in cellular assays although their prodrug moieties were designed to produce high levels of triphosphate in the liver. Since peripheral blood mononuclear cells (PBMCs) are one of the major targets of dengue virus, different prodrug moieties were designed to effectively deliver 2\'-deoxy-2\'-fluoro-2\'-C-methylguanosine monophosphate prodrugs and their corresponding triphosphates into PBMCs after oral administration. We identified a cyclic phosphoramidate prodrug 17 demonstrating a well-balanced anti-dengue cellular activity and in vitro stability profiles. We further determined the PBMCs concentration of active triphosphate needed to inhibit 50% virus replication (TP50). Compound 17 was assessed in AG129 mouse model and demonstrated 1.6- and 2.2-log viremia reduction at 100 and 300 mg/kg BID, respectively. At 100 mg/kg BID, the terminal triphosphate concentration in PBMCs reached above TP50, demonstrating TP50 as the target exposure for efficacy. In dogs, oral administration of 17 resulted in high PBMCs triphosphate level, exceeding TP50 at 10 mg/kg. Unfortunately, two-week dog toxicity studies at 30, 100, and 300 mg/kg/day showed that No Observed Adverse Effect Level (NOAEL) could not be achieved due to pulmonary inflammation and hemorrhage. The preclinical safety results suspended further development of 17 Nevertheless, present work has proven the concept that an efficacious monophosphate nucleoside prodrug could be developed for the potential treatment of dengue infection.
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