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Prodrug Strategies to Improve the Solubility of the HCV NS5A Inhibitor Pibrentasvir (ABT-530).
- Source :
-
Journal of medicinal chemistry [J Med Chem] 2020 Oct 08; Vol. 63 (19), pp. 11034-11044. Date of Electronic Publication: 2020 Sep 17. - Publication Year :
- 2020
-
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.
- Subjects :
- Animals
Antiviral Agents pharmacokinetics
Antiviral Agents pharmacology
Area Under Curve
Benzimidazoles pharmacokinetics
Benzimidazoles pharmacology
Dogs
Mice
Prodrugs pharmacology
Pyrrolidines pharmacokinetics
Pyrrolidines pharmacology
Solubility
Antiviral Agents chemistry
Benzimidazoles chemistry
Prodrugs chemistry
Pyrrolidines chemistry
Viral Nonstructural Proteins antagonists & inhibitors
Subjects
Details
- Language :
- English
- ISSN :
- 1520-4804
- Volume :
- 63
- Issue :
- 19
- Database :
- MEDLINE
- Journal :
- Journal of medicinal chemistry
- Publication Type :
- Academic Journal
- Accession number :
- 32881503
- Full Text :
- https://doi.org/10.1021/acs.jmedchem.0c00956