The effect of phenyl substituents on the release rates of esterase-sensitive coumarin-based prodrugs

A coumarin-based prodrug system has been recently developed in our laborato ry for the preparation of esterase-sensitive prodrugs of amines, peptides, and peptidomimetics. The drug release rates from this prodrug system were f ound to be dependent on the structural features of the drug moiety. In cert ain cases, the release can be undesirably slow for drugs that are secondary amines with relatively high pK(a)'s. Aimed at finding ways to manipulate t he release rates to suit the need of different drugs, we have examined the effect of the phenyl ring substitutions on the release kinetics of such pro drugs and found that appropriately positioned alkyl substituents on the phe nyl ring could help to facilitate the release by as much as 16-fold. Theref ore, introduction of alkyl substituents on the phenyl ring should allow us to manipulate the release rates and, therefore, time profiles for different drugs.