Prodrug Strategies to Improve the Solubility of the HCV NS5A Inhibitor Pibrentasvir (ABT-530)

A research program to discover solubilizing
prodrugs of the HCV
NS5A inhibitor pibrentasvir (PIB) identified phosphomethyl analog 2 and trimethyl-lock (TML) prodrug 9. The prodrug
moiety is attached to a benzimidazole nitrogen atom via an oxymethyl
linkage to allow for rapid and complete release of the drug for absorption
following phosphate removal by intestinal alkaline phosphatase. These
prodrugs have good hydrolytic stability properties and improved solubility
compared to PIB, both in aqueous buffer (pH 7) and FESSIF (pH 5).
TML prodrug 9 provided superior in vivo performance,
delivering high plasma concentrations of PIB in PK studies conducted
in mice, dogs, and monkeys. The improved dissolution properties of
these phosphate prodrugs provide them the potential to simplify drug
dosage forms for PIB-containing HCV therapy.