Prodrugs as empowering tools in drug discovery and development: recent strategic applications of drug delivery solutions to mitigate challenges associated with lead compounds and drug candidates.

The delivery of a drug to a specific organ or tissue at an efficacious concentration is the pharmacokinetic (PK) hallmark of promoting effective pharmacological action at a target site with an acceptable safety profile. Sub-optimal pharmaceutical or ADME profiles of drug candidates, which can often be a function of inherently poor physicochemical properties, pose significant challenges to drug discovery and development teams and may contribute to high compound attrition rates. Medicinal chemists have exploited prodrugs as an informed strategy to productively enhance the profiles of new chemical entities by optimizing the physicochemical, biopharmaceutical, and pharmacokinetic properties as well as selectively delivering a molecule to the site of action as a means of addressing a range of limitations. While discovery scientists have traditionally employed prodrugs to improve solubility and membrane permeability, the growing sophistication of prodrug technologies has enabled a significant expansion of their scope and applications as an empowering tool to mitigate a broad range of drug delivery challenges. Prodrugs have emerged as successful solutions to resolve non-linear exposure, inadequate exposure to support toxicological studies, pH-dependent absorption, high pill burden, formulation challenges, lack of feasibility of developing solid and liquid dosage forms, first-pass metabolism, high dosing frequency translating to reduced patient compliance and poor site-specific drug delivery. During the period 2012-2022, the US Food and Drug Administration (FDA) approved 50 prodrugs, which amounts to 13% of approved small molecule drugs, reflecting both the importance and success of implementing prodrug approaches in the pursuit of developing safe and effective drugs to address unmet medical needs.