Strategies in the design of solution-stable, water-soluble prodrugs I: a physical-organic approach to pro-moiety selection for 21-esters of corticosteroids.
The ideal water-soluble prodrug should exhibit sufficient aqueous solution stability to allow long-term storage of its solutions (i.e., 2 years at room temperature) and yet should be converted rapidly in vivo to the active parent drug--two severe and seemingly conflicting demands which limit the utility of many common solubilizing pro-moieties. For example, succinate esters, which are commonly utilized as water-soluble prodrugs, are unstable in solution and may undergo slow and incomplete bioconversion in vivo. In this study, the solution stability problems associated with 21-esters of corticosteroids are reviewed. It is concluded that the most important reaction limiting shelf life is ester hydrolysis. From a consideration of the influence of molecular structure on ester reactivity, a strategy for the design of solution-stable, water-soluble prodrugs of corticosteroids has been developed. Two key requirements for dilute solution stability are high solubility at the pH of optimum stability and appropriate design of the pH-rate profile. Several 21-esters of methylprednisolone have been synthesized, and the rates of their aqueous solution hydrolysis have been determined to test the strategy. Compounds exhibiting estimated shelf lives in dilute solution of greater than 2 years at 25 degrees C have been identified.
D000305:Adrenal Cortex Hormones / Q000138:chemical synthesis*; D002384:Catalysis; D055598:Chemical Phenomena; D002626:Chemistry, Pharmaceutical; D002627:Chemistry, Physical; D004355:Drug Stability; D006863:Hydrogen-Ion Concentration; D006868:Hydrolysis; D007700:Kinetics; D008775:Methylprednisolone / Q000031:analogs & derivatives / Q000138:chemical synthesis; D012995:Solubility
D000305:Adrenal Cortex Hormones; D008775:Methylprednisolone