Sequentially labile water-soluble prodrugs of alprazolam

Abstract

A 1,4-benzodiazepine analogue alprazolam (1) undergoes ring-opening hydrolysis under acidic conditions to form a triazolobenzophenone (2). At a neutral pH, 2 rapidly and quantitatively cyclizes back to 1. This facile reversible reaction was utilized in developing water-soluble prodrugs of 1 in which the "solubility anchoring" acyl moieties are formyl, acetyl, succinyl, glycyl, leucyl, and gamma-aminobutyryl groups. These compounds were prepared directly from 2 and corresponding acids through DCC coupling in a 1:1 mixture of H2O and THF. They should be stable in aqueous media at room temperature. Promoieties used should be nontoxic at an intended dose level. In vitro human serum hydrolysis study showed that only glycyl and leucyl amides were able to regenerate 1 within a reasonable period of time. Ex vivo competitive receptor binding assay in mice with [3H]flunitrazepam indicated that leucyl amide prodrug should be able to produce a rapid onset of the intrinsic central nervous system activity of 1 when parenterally administered. For all compounds studied, the final outcome of the biological response appears to be kinetically controlled, rather than by an unfavorable equilibrium, particularly by the first step in which the amide bond is hydrolyzed in vivo.

Synthesis of 3,4,5-Trisubstituted-1,2,4-triazoles

“…These compounds were in fact considered as water-soluble prodrugs which could undergo an enzymatic hydrolysis of the peptide bond followed by a chemical cyclization in physiological conditions to give the triazolobenzodiazepine scaffold 139 (Scheme 32). As an example, Cho et al 112 reported the use of a reversible 1,4benzodiazepine ring-opening reaction of Alprazolam.…”

The use of prodrugs as drugs of abuse

“…While alprazolam triazolobenzophenone was originally developed as simultaneously a metabolite and prodrug of alprazolam—cyclizing back to alprazolam at neutral pH, suffering ring‐opening hydrolysis in acidic conditions to it triazolobenzophenone counterpart—there are few reports of its seizure and it is understood that its effects are similar to those of alprazolam (Cho et al, 1986; Orsolini et al, 2020).…”

In vitro and ex vivo evaluation of cyclic aminoalkyl benzilates as potential emission tomography ligands for the muscarinic receptor

“…To assess brain penetration of the compunds, an ex vivo assay patterned on that used by Cho et al (1986) and Sethy et al (1987) was conducted. This ex vivo assay consisted of injection of unlabeled ligand into an animal followed by sacrifice and use of an in vitro binding assay to measure residual [3 H]QNB binding to brain homogenates.…”

“…1). It was hoped that a combination of in vitro and ex vivo assays (Cho et al, 1986;Sethy et al, 1987) would provide answers to these questions and allow selection of promising candidates without resorting to expensive and time consuming radiosynthesis of each compound under initial consideration.…”