Chemistry-enabled drug delivery (prodrugs): recent progress and challenges

• Prodrugs average 10% of the total number of small molecules launched in the USA.
• Patent life can be extended 6–7 years by prodrugs, salts and other forms, it is claimed.
• Recently launched prodrugs were designed to enhance bioavailability.
• CYP bioconversion and carrier-mediated transport are popular prodrug strategies.
• Prodrugs should be a key part of the armamentarium of the discovery scientist.

Prodrugs can be used to enhance the properties of an active pharmaceutical ingredient or drug, generally by improving solubility and/or permeability of the compound. However, discovery teams duly spend considerable time and resources on structure–activity optimization and formulation-enabled drug delivery technologies to achieve the target exposures and biopharmaceutical properties, when early implementation of prodrugs could lead to an improved drug molecule. The goal of this review is to provide an overview of the achievements during the past few years in developing prodrugs and highlighting the challenges of following this approach.