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Coupling of an Acyl Migration Prodrug Strategy with Bio-activation To Improve Oral Delivery of the HIV-1 Protease Inhibitor Atazanavir.
- Source :
-
Journal of medicinal chemistry [J Med Chem] 2018 May 10; Vol. 61 (9), pp. 4176-4188. Date of Electronic Publication: 2018 Apr 25. - Publication Year :
- 2018
-
Abstract
- HIV-1 protease inhibitors (PIs), which include atazanavir (ATV, 1), remain important medicines to treat HIV-1 infection. However, they are characterized by poor oral bioavailability and a need for boosting with a pharmacokinetic enhancer, which results in additional drug-drug interactions that are sometimes difficult to manage. We investigated a chemo-activated, acyl migration-based prodrug design approach to improve the pharmacokinetic profile of 1 but failed to obtain improved oral bioavailability over dosing the parent drug in rats. This strategy was refined by conjugating the amine with a promoiety designed to undergo bio-activation, as a means of modulating the subsequent chemo-activation. This culminated in a lead prodrug that (1) yielded substantially better oral drug delivery of 1 when compared to the parent itself, the simple acyl migration-based prodrug, and the corresponding simple l-Val prodrug, (2) acted as a depot which resulted in a sustained release of the parent drug in vivo, and (3) offered the benefit of mitigating the pH-dependent absorption associated with 1, thereby potentially reducing the risk of decreased bioavailability with concurrent use of stomach-acid-reducing drugs.
- Subjects :
- Administration, Oral
Animals
Atazanavir Sulfate administration & dosage
Atazanavir Sulfate pharmacokinetics
Biological Availability
Fatty Acid Transport Proteins metabolism
HIV Protease Inhibitors administration & dosage
HIV Protease Inhibitors pharmacokinetics
Rats
Rats, Sprague-Dawley
Symporters metabolism
Tissue Distribution
Atazanavir Sulfate metabolism
Atazanavir Sulfate pharmacology
HIV Protease Inhibitors metabolism
HIV Protease Inhibitors pharmacology
Prodrugs metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 1520-4804
- Volume :
- 61
- Issue :
- 9
- Database :
- MEDLINE
- Journal :
- Journal of medicinal chemistry
- Publication Type :
- Academic Journal
- Accession number :
- 29693401
- Full Text :
- https://doi.org/10.1021/acs.jmedchem.8b00277