Recent research efforts have been directed at developing targeted prodrugs to replace the classical prodrugs. The use of this approach has accelerated following the emergence of encouraging results from several studies on targeted prodrugs that have highlighted their higher efficiency and improved safety profiles. Targeted prodrug delivery is now considered more than a chemical modification method. It is an applicable and promising approach and, in the future, better knowledge and wide application of this approach may be attained which may pave the way for more forward-thinking and creative techniques.
DFT calculations at B3LYP/6-31G(d,p) for intramolecular proton transfer in Kirby's enzyme models 1-7 demonstrated that the reaction rate is dependent on the distance between the two reacting centers, rGM, and the hydrogen bonding angle, α, and the rate of the reaction is linearly correlated with rGM and α. Based on these calculation results three simvastatin prodrugs were designed with the potential to provide simvastatin with higher bioavailability. For example, based on the calculated log EM for the three proposed prodrugs, the interconversion of simvastatin prodrug ProD 3 to simvastatin is predicted to be about 10 times faster than that of either simvastatin prodrug ProD 1 or simvastatin ProD 2. Hence, the rate by which the prodrug releases the statin drug can be determined according to the structural features of the promoiety (Kirby's enzyme model).
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