Amine Prodrugs Which Utilize Hydroxy Amide Lactonization. II. A Potential Esterase-Sensitive Amide Prodrug

In an effort to develop esterase-sensitive pro-prodrugs for amines, an amide derivative of 3-(2-acetoxy-4,6-dimethylphenyl)-3,3- dimethylpropionic acid (4-methoxyaniline amide (8) was synthesized and its stability investigated. This esterifled hydroxy amide was found under all conditions to degrade via a two-step process initiated by acetyl ester hydrolysis generating the hydroxy amide intermediate 9a. The lactonization of this intermediate 9a in the second step resulted in the formation of 4-methoxyaniline (10) and 4,4,5,7-tetramethyl-3,4-dihydrocoumarin (la). The pro-prodrug 8 was observed to possess the following half-lives at 37°C under various conditions: 4030 min in phosphate buffer (50 mM, µ = 0.15) fixed to pH 7.4, 11.9 min in the same buffer containing a porcine liver esterase, 53.7 min in plasma, and 475 min in plasma containing diisopropylfluorophosphate. These results suggest that in a biological milieu the ester hydrolysis will occur by the enzymic hydrolysis rather than the chemical hydrolysis and that the enzymic hydrolysis of 8 in plasma is due, in part, to the action of serine-dependent esterases.