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

Various alkyl esters of 6-methoxy-2-naphthylacetic acid (6-MNA), the active metabolite of nabumetone.(1), have been synthesized with the objective of obtaining the prodrugs that would release the active drug only. To assess their prodrug potential, these esters are evaluated for solubility, partition coefficient and capacity factors. The correlation between the partition coefficients, capacity factors and ester chain lengths are established. The hydrolysis of these prodrugs has been studied at various temperatures and pseudo first order rate constants and half lives in aqueous buffer, human plasma and liver homogenate were determined. The hydrolysis of the representative methyl ester has been studied in various buffers of pH range 1.2 to 9. Second order rate constants for specific acid and specific base catalyzed hydrolysis and first order rate constant for spontaneous hydrolysis are determined. The esters show maximum stability between pH 4-5 and are easily cleavable in liver homogenate.