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(Carbonyl)oxyalkyl linker-based amino acid prodrugs of the HIV-1 protease inhibitor atazanavir that enhance oral bioavailability and plasma trough concentration.
- Source :
-
European journal of medicinal chemistry [Eur J Med Chem] 2020 Dec 01; Vol. 207, pp. 112749. Date of Electronic Publication: 2020 Aug 21. - Publication Year :
- 2020
-
Abstract
- We describe the design, synthesis and pharmacokinetic (PK) evaluation of a series of amino acid-based prodrugs of the HIV-1 protease inhibitor atazanavir (1) derivatized on the pharmacophoric secondary alcohol using a (carbonyl)oxyalkyl linker. Prodrugs of 1 incorporating simple (carbonyl)oxyalkyl-based linkers and a primary amine in the promoiety were found to exhibit low chemical stability. However, chemical stability was improved by modifying the primary amine moiety to a tertiary amine, resulting in a 2-fold enhancement of exposure in rats following oral dosing compared to dosing of the parent drug 1. Further refinement of the linker resulted in the discovery of 22 as a prodrug that delivered the parent 1 to rat plasma with a 5-fold higher AUC and 67-fold higher C <subscript>24</subscript> when compared to oral administration of the parent drug. The PK profile of 22 indicated that plasma levels of this prodrug were higher than that of the parent, providing a more sustained release of 1 in vivo.<br />Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.<br /> (Copyright © 2020 Elsevier Masson SAS. All rights reserved.)
- Subjects :
- Alkylation
Amines chemistry
Amino Acids metabolism
Atazanavir Sulfate blood
Atazanavir Sulfate metabolism
Biological Availability
Drug Stability
HIV Protease Inhibitors blood
HIV Protease Inhibitors metabolism
Humans
Prodrugs metabolism
Amino Acids chemistry
Atazanavir Sulfate pharmacokinetics
Atazanavir Sulfate pharmacology
HIV Protease metabolism
HIV Protease Inhibitors pharmacokinetics
HIV Protease Inhibitors pharmacology
Prodrugs chemistry
Subjects
Details
- Language :
- English
- ISSN :
- 1768-3254
- Volume :
- 207
- Database :
- MEDLINE
- Journal :
- European journal of medicinal chemistry
- Publication Type :
- Academic Journal
- Accession number :
- 33065417
- Full Text :
- https://doi.org/10.1016/j.ejmech.2020.112749