Design, Synthesis, and Pharmacokinetic Evaluation of Phosphate and Amino Acid Ester Prodrugs for Improving the Oral Bioavailability of the HIV-1 Protease Inhibitor Atazanavir

Abstract

Phosphate and amino acid prodrugs of the HIV-1 protease inhibitor (PI) atazanavir (1) were prepared and evaluated to address solubility and absorption limitations. While the phosphate prodrug failed to release 1 in rats, the introduction of a methylene spacer facilitated prodrug activation, but parent exposure was lower than that following direct administration of 1. Val amino acid and Val-Val dipeptides imparted low plasma exposure of the parent, although the exposure of the prodrugs was high, reflecting good absorption. Screening of additional amino acids resulted in the identification of an L-Phe ester that offered an improved exposure of 1 and reduced levels of the circulating prodrug. Further molecular editing focusing on the linker design culminated in the discovery of the self-immolative L-Phe-Sar dipeptide derivative 74 that gave fourfold improved AUC and eight-fold higher C trough values of 1 compared with oral administration of the drug itself, demonstrating a successful prodrug approach to the oral delivery of 1.

Separation and preparative purification ofl‐ andd‐valine ester: Diastereomeric conjugates of atazanavir using a combination of 2‐propanol and acetonitrile in reversed‐phase high‐performance liquid chromatography

“…Solvent 2‐propanol has been used as an organic modifier for few critical separation in analytical reversed‐phase HPLC [25–27] but its application for preparative purifications is very limited because of high back pressure it may generate after mixing with aqueous buffer. Encouraged with its reported application in analytical reversed‐phase HPLC, it was decided to try the combination of ACN/2‐propanol for the purification of diastereomers 4 and 5 .…”

“…The use of 2-propanol as an alternative organic modifier to ACN has also been reported for a few critical separations in reversed-phase HPLC for analytical HPLC methods. [25,26]. The lower polarity and higher elutropic strength of 2-propanol (3.9 and 8.1) compared to ACN (5.8 and 3.1) and methanol (5.1 and 1.0) are helpful to control the elution and retention of the compound on the stationary phase for efficient separation [27][28][29][30].…”

“…Applications of prodrugs as tools for effective drug delivery have been well‐documented in the literature [24]. In an attempt to improve the pharmacokinetic profile of 1 , prodrug strategies have recently been examined [25]. One of the approaches was to investigate l ‐ and d ‐valine based prodrugs.…”

Stimulus-Responsive Nanomedicines for Disease Diagnosis and Treatment

“…β-galactoside and β-glucuronide are functional groups that can be cleaved by β-galactosidase and β-glucuronidase, respectively, and these two functional groups can also be combined with other self-immolative linkers [ 191 , 192 , 193 , 194 ]. In addition, dibenzyl phosphate derivatives are also used for enzymatic (alkaline phosphatase) self-immolative design for the delivery and release of fluorescent probes and prodrugs [ 195 , 196 ]. Enzymatically activated self-immolation is usually slow and requires synergy with other self-immolative linkers.…”

<p>Self-Microemulsifying Drug Delivery System for Improved Oral Delivery and Hypnotic Efficacy of Ferulic Acid</p>

“…Various strategies to overcome the low oral bioavailability of drugs have been investigated, including structural modifications, 18 formation of polymer-drug complexes, 19,20 and the use of GI absorption enhancers. 21 These strategies may improve the oral bioavailability of drugs possessing high GI stability, but are not suitable for the oral delivery of FA as it is rapidly metabolized after entering the GI tract.…”