Coumarin-based prodrugs. Part 3: Structural effects on the release kinetics of esterase-sensitive prodrugs of amines

To study the structural effects on the release kinetics of a coumarin- based esterase-sensitive prodrug system, two series of compounds with varying structural features of the ester 'trigger' part and the amine 'drug' part were synthesized. The half-lives of the nine model prodrugs in the presence of porcine liver esterase ranged from about 2 min to 190 min. The steric bulkiness of the acyl group seems to have only a very minor effect on the half-lives of the esterase-triggered release of amines from the model prodrugs. The rate of the lactonization depends on the steric and electronic properties of the amine moiety.