Glycolamide esters of 6-methoxy-2-naphthylacetic acid as potential prodrugs - physicochemical properties, chemical stability and enzymatic hydrolysis

Abstract

Various glycolamide ester prodrugs of 6-MNA (I), an active metabolite of nabumetone (II), were synthesised to obtain NSAIDs with improved therapeutic index. To assess their suitability as prodrugs, these derivatives were evaluated for physicochemical properties, chemical stability and enzymatic hydrolysis in 80% human plasma. A number of these ester derivatives possessed physicochemical properties required for oral absorption (log P ≥ 2, solubility ≥ 10 μg/ ml). These esters were sufficiently stable in 0.05 M phosphate buffer of pH 7.4 at 37°C (half-lives 16–473 h). The disubstituted glycolamide esters XII-XXII were more stable than monosubstituted glycolamide esters IV-XI. Compound XII was also subjected to hydrolytic studies over the pH range 1.2–9.0 at 70°C and from the pH-rate profile, the pH of maximum stability was found to be 4.34 (4–5). At pH 4.5 compound XII showed a shelf life of 1.12 years at 20°C as determined from accelerated studies using the Arrhenius equation. The ester derivatives were quantitatively converted to 6-MNA very rapidly in human plasma at 37°C and pH 7.4 Comparison with chemical stability data shows that the intrinsic reactivity of esters has no effect on their enzymatic reactivity. The chemically most stable N,N-disubstituted glycolamide esters were better substrates for plasma enzymes (half-lives 7–83 s) compared to the monosubstituted glycolamide esters (half-lives 168–809 s). It is concluded that these derivatives possess many of the ideal properties of prodrugs and esterification of 6-MNA with substituted 2-hydroxyacetamides may be a potentially useful prodrug approach.