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Amine Prodrugs Which Utilize Hydroxy Amide Lactonization. II. A Potential Esterase-Sensitive Amide Prodrug
Authors:Amsberry  Kent L.  Gerstenberger  A. Elise  Borchardt   Ronald T.
Affiliation:(1) Department of Pharmaceutical Chemistry, University of Kansas, Lawrence, Kansas, 66045;(2) Present address: Bristol-Myers Squibb Pharmaceutical Research Institute, New Brunswick, New Jersey, 08903-0191
Abstract:In an effort to develop esterase-sensitive pro-prodrugs for amines, an amide derivative of 3-(2prime-acetoxy-4prime,6prime-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.
Keywords:pro-prodrug  esterified hydroxy amide  esterase  lactonization
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