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Improving Drug Delivery While Tailoring Prodrug Activation to Modulate C max and C min by Optimization of (Carbonyl)oxyalkyl Linker-Based Prodrugs of Atazanavir.
- Source :
-
Journal of medicinal chemistry [J Med Chem] 2022 Aug 25; Vol. 65 (16), pp. 11150-11176. Date of Electronic Publication: 2022 Aug 11. - Publication Year :
- 2022
-
Abstract
- Structure-property relationships associated with a series of (carbonyl)oxyalkyl amino acid ester prodrugs of the marketed HIV-1 protease inhibitor atazanavir ( 1 ), designed to enhance the systemic drug delivery, were examined. Compared to previously reported prodrugs, optimized candidates delivered significantly enhanced plasma exposure and trough concentration ( C <subscript>min</subscript> at 24 h) of 1 in rats while revealing differentiated PK paradigms based on the kinetics of prodrug activation and drug release. Prodrugs incorporating primary amine-containing amino acid promoieties offered the benefit of rapid bioactivation that translated into low circulating levels of the prodrug while delivering a high C <subscript>max</subscript> value of 1 . Interestingly, the kinetic profile of prodrug cleavage could be tailored for slower activation by structural modification of the amino terminus to either a tertiary amine or a dipeptide motif, which conferred a circulating depot of the prodrug that orchestrated a sustained release of 1 along with substantially reduced C <subscript>max</subscript> and a further enhanced C <subscript>min</subscript> .
Details
- Language :
- English
- ISSN :
- 1520-4804
- Volume :
- 65
- Issue :
- 16
- Database :
- MEDLINE
- Journal :
- Journal of medicinal chemistry
- Publication Type :
- Academic Journal
- Accession number :
- 35952307
- Full Text :
- https://doi.org/10.1021/acs.jmedchem.2c00632