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

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 min 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 max 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 max and a further enhanced C min.

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 expansion of the structure–property relationship of this class of prodrugs led to optimized candidates 4v and 4w that substantially enhanced both AUC and C min of 3l . 213 The PK profiles of 4u–4w indicated that the circulating prodrugs acted as depots to provide a sustained release of 3l , representing a further advancement in the oral delivery of 3l over the previously-studied prodrugs. The examples provided by 4u–4w demonstrate the successful application of a prodrug strategy that mitigates not only the barriers to oral absorption of 3l , but also provides a measure of controlled parent release, in which the prodrug acts as a circulating depot of the parent that is released in a measured fashion by hydrolytic enzymes.…”