Coupling of an Acyl Migration Prodrug Strategy with Bio-activation To Improve Oral Delivery of the HIV-1 Protease Inhibitor Atazanavir

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.

Transacylation in Ferrocenoyl-Purines. NMR and Computational Study of the Isomerization Mechanism

“…The N7 / N9 -transferrocenoylation in purines may be classified as an intramolecular acyl migration, which is of special importance in organic and medicinal chemistry. An acyl shift occurs frequently in carbohydrates, lipids, or peptides − and serves as a reaction channel in prodrug design and various synthetic strategies. − So far, however, only a few studies have coupled experimental and computational methods to clarify the underlying mechanism. In this work, a cluster of earlier relevant examples, including imidazole rings and benzotriazoles, , has been expanded to purines.…”

The Application of Isoacyl Structural Motifs in Prodrug Design and Peptide Chemistry

“…More recently,S ubbaiah et al reported their work on improving the oral bioavailability of Atazanavir;a nH IV-1 PR inhibitor (Scheme 2D). [36] This isoacyl prodrug was prepared with a capped isoacyl motif. An esterase-mediated removal of the valine triggered the subsequent releaseo fi sobutyric aldehyde and carbon dioxide, and eventually the free isoacyl motif, which simultaneously underwent the O-to-N acyl shift to provide Atazanavir.…”

“…More recently, Subbaiah et al. reported their work on improving the oral bioavailability of Atazanavir; an HIV‐1 PR inhibitor (Scheme D) . This isoacyl prodrug was prepared with a capped isoacyl motif.…”

Synthesis and Characterization of Long-Acting Darunavir Prodrugs

“…While such prodrug approaches were previously explored in attempts to improve absorption, distribution, metabolism and drug excretion (ADME) none have yet to be applied to the generation of reservoir targeted LA DRV (30)(31)(32)(33). Prior efforts included, but were not limited to, carrier-mediated drug delivery approaches that incorporate amino acids to minimize p-glycoprotein efflux and mitigate first pass metabolism (30,34). Notably, extensive prodrug approaches have led to development and approval of fosamprenavir, a phosphorylated water-soluble prodrug of amprenavir (35).…”

“…One strategy is utilizing prodrugs to extend the half-life and biodistribution of the agent. While such prodrug approaches were previously explored in attempts to improve absorption, distribution, metabolism, and drug excretion (ADME), none have yet to be applied to the generation of reservoir-targeted LA DRV. − Prior efforts included, but were not limited to, carrier-mediated drug delivery approaches that incorporate amino acids to minimize p-glycoprotein efflux and mitigate first pass metabolism. , Notably, extensive prodrug approaches have led to development and approval of fosamprenavir, a phosphorylated water-soluble prodrug of amprenavir . Various fatty ester prodrugs of indinavir and saquinavir have been described but are significantly less potent compared to the parent drugs .…”