(Carbonyl)oxyalkyl linker-based amino acid prodrugs of the HIV-1 protease inhibitor atazanavir that enhance oral bioavailability and plasma trough concentration

Improving Drug Delivery While Tailoring Prodrug Activation to Modulate Cmax and Cmin by Optimization of (Carbonyl)oxyalkyl Linker-Based Prodrugs of Atazanavir

“…In those cases, where both isomers of the same amino acid were tested, the second eluting isomer produced higher plasma exposure than the first eluting isomer. Prodrugs 3s [L-Val (isomer-2)], 3y [ACC (isomer-2)], 3z [β-Ala (isomer-2)], and 3ac [ATBA (isomer-2)] afforded significantly enhanced plasma exposure (AUC last ) of 1 in the range of 6.7- to 9.5-fold, values that exceeded the AUC profiles of previously reported prodrug candidates, which offered improvements of 4- to 5.1-fold enhanced exposure of 1 . − While the cyclopropyl-bearing amino acid prodrugs 3x and 3y gave better total exposure (22.2-fold over the parent) of parent and prodrug than the other α-amino acid-based prodrugs (0.3 to 5.1-fold), the β-amino acid prodrug 3ac gave the highest total exposure (27-fold) of all of the prodrugs that were examined in this phase of the study. Although prodrugs such as 3p , 3q and 3u – 3x were unable to deliver improved trough concentrations of 1 measured at 24 h post-dosing, other prodrugs displayed 4.8- to 70-fold higher C 24 values of 1 .…”

“…The limitations associated with the physicochemical properties of 1 have stimulated an investigation of the potential of prodrug strategies to improve the systemic delivery of the PI. − The application of prodrug approaches to successfully mitigate drug delivery issues of marketed drugs, clinical candidates, and lead molecules is well-documented. − However, applications of prodrugs, in which a (carbonyl)­oxyalkyl-based linker is attached to the pharmacophoric secondary alcohol moiety of HIV-1 PIs or a hydroxy substituent of drugs from other therapeutic classes, have been explored only sparingly as an approach to addressing drug delivery challenges . A key observation from early prodrug studies was the failure of most prodrug moieties that were attached directly to the pharmacophoric 2° alcohol of 1 to deliver significantly improved oral bioavailability of 1 due to inefficient bioactivation in vivo .…”

Prodrugs as empowering tools in drug discovery and development: recent strategic applications of drug delivery solutions to mitigate challenges associated with lead compounds and drug candidates

“…Subsequent optimization of the delivery of 3l focused on the application of (carbonyl)oxyalkyl-based immolating linker design as a 4th generation prodrug design strategy (Table 27). 73 While the structurally simplest iterations of this approach suffered from inadequate chemical stability, the introduction of steric shielding to the acetal carbon atom and replacing the primary amine in the promoiety with a tertiary amine ultimately afforded 4u as a molecule that addressed the shortcomings. This prodrug improved the AUC and C 24h of 3l in rats by 5- and 67-fold, respectively, compared to oral administration of the parent molecule.…”

“…70,71 Prodrug strategies have been explored to improve oral bioavailability and reduce intersubject PK variability by attenuating or bypassing hepatic metabolism. 65,70–73…”

Prodrug Therapies for Infectious and Neurodegenerative Diseases

“…However, many of these prodrug developments have reported a marked loss of antiretroviral activity due to the stable chemical modifications conjugated to a critical component of the pharmacophore [ 123 ]. Subbaiah et al developed a (carbonyl)oxyalkyl linker-based amino acid prodrug of atazanavir and reported a five-fold higher AUC that was attained after oral administration in rats than that which was attained by the orally administered native drug [ 124 ]. However, PK assessment concluded at 24 h, thus the sustainability of antiretroviral activity over a longer time could not be substantiated.…”