QSAR analysis of chemical and serum-catalyzed hydrolysis of phenyl ester prodrugs of nipecotic acid

Abstract

Chemical and serum-catalyzed hydrolysis of an appropriately designed series of substituted X-phenyl esters of nipecotic acid were studied. A pseudo-first-order kinetics has been observed in the rates of both kinds of hydrolysis and for the serum-catalyzed hydrolysis the following quantitative structure-activity relationship was derived: log t 1 2 = −0.99σ − − 0.21π + 2.25 . In this equation t 1 2 is the half-life, σ − is the “trough resonance” Hammett constant and π is the Hansch hydrophobic constant. The correlation equation pointed out the great influence of the electronic properties of X-substituents on the rate of hydrolysis which is only slightly influenced by the hydrophobicity of X. A group of suitably selected esters 4 was tested for antagonism of convulsions and death induced by bicuculline and a correlation between in vitro rates of enzymatic hydrolysis and anticonvulsant activity could be found. The results have been discussed in relation to the design of ester prodrugs of polar GABA-mimetics and other CNS-active agents.