Synthesis, stability, and pharmacological evaluation of nipecotic acid prodrugs

Nipecotic acid (1), one of the most potent in vitro inhibitors of neuronal and glial gamma-amino butyric acid (GABA) uptake, is inactive as an anticonvulsant when administered systemically. To obtain in vivo active prodrugs of (1), we synthesized four new nipecotic acid esters (3-6), which were obtained by chemical conjugation with glucose, galactose, and tyrosine. These compounds were assayed to evaluate their in vitro chemical and enzymatic hydrolysis. In addition, their anticonvulsant activity was evaluated in vivo in Diluted Brown Agouti (DBA)/2 mice, an excellent animal model for the study of new anticonvulsant drugs. Esters (3-6) appeared stable, at various temperatures, in a pH 7.4 buffered solution and showed susceptibility to undergoing in vitro enzymatic hydrolysis. Intraperitoneally injected nipecotic acid (1) and esters (3-5) did not protect mice against audiogenic seizures; conversely, nipecotic tyrosine ester (6) showed a significant dose-dependent anticonvulsant activity. The in vivo protective activity of the ester (6) and the inefficiency of nipecotic acid (1) in the same experimental conditions suggest that this ester prodrug could be actively transported intact across the blood-brain barrier, beyond which it could be hydrolyzed.