Current and Emerging Prodrug Strategies

An analysis of recent prodrugs reported in the literature is discussed. The range of strategies includes ProTide technologies, esters, phosphates, cell-targeting approaches, pH-dependent approaches, and newer technologies such as photo- and radiation-activated prodrugs. Many successful prodrug approaches have been a result of the first three examples, which appear to be well established. One area of significant impact for prodrug technology has been with anti-infectives. This area is discussed in detail with learnings and innovations that can be applied to other disease areas. Finally, the prodrug strategy is discussed in the context of both reactive and proactive applications. If used as a rescue strategy for a failed clinical candidate, it can be potentially costly and time-consuming. Proactive prodrug strategies should be considered in the early phase of drug discovery programs, especially in cases in which chemotype properties or target-based risks may compromise the desired route of administration.