| Literature DB >> 32881503 |
John T Randolph1, Eric A Voight1, Stephen N Greszler1, Brice E Uno1, James N Newton1, Kenneth M Gleason1, DeAnne Stolarik1, Cecilia Van Handel1, Daniel A J Bow1, David A DeGoey1.
Abstract
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.Entities:
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Year: 2020 PMID： 32881503 DOI： 10.1021/acs.jmedchem.0c00956
Source DB: PubMed Journal: J Med Chem ISSN： 0022-2623 Impact factor: 7.446