Hydrolysis of nipecotic acid phenyl esters.

The synthesis and anticonvulsant activity of nipecotic acid esters (1a-1f) have been previously reported. It was thought that these prodrug esters underwent hydrolytic conversion to 1 which inhibited GABA uptake, and that both 1 and an intact ester may have caused inhibition of GABA uptake which resulted in the anticonvulsant activity. There is, however, no stability data available to help evaluate these effects. We have determined degradation half-lives (t 1/2) of these phenyl esters dissolved in 10% serum solution or in pH 7.4 buffer (ionic strength = 0.25 adjusted with KCl) at 37 degrees C by monitoring the appearance of a phenolic compound for a period of 12 h with an HPLC method. Utilizing a published method, in vitro [14C]GABA uptake was measured. Results show that the hydrolysis rate in 10% serum solution was faster than that in buffer solution and that half-lives varied between 0.20 and 3.84 h. The uptake inhibition varied between 8.2 and 41.7% at 0.02 mM concentration, and percent GABA uptake inhibition correlated with log t 1/2 (r = -0.9827, p = 0.00045, based on a t test). Our data suggest that at concentrations ranging from 0.02 to 1 mM, inhibition of GABA uptake is mainly due to 1 formed after hydrolysis of 1a-1f.