Prodrugs: Strategic Deployment, Metabolic Considerations, and Chemical Design Principles

Abstract

This article begins by providing a brief history about prodrugs, and then delineates their specific definition while contrasting them to “regular” drugs and to soft drugs. It continues by discussing their strategic deployment during today's drug discovery and development paradigm, including their union with biological molecules to produce antibody–drug conjugates (ADCs) which are becoming extremely popular as new molecular entities (NMEs). Metabolic considerations focus upon hydrolytic processes while emphasizing, in particular, the important roles that are often played by the carboxylesterases. Design aspects include both a listing of commonly deployed functional groups and a discussion of how to impact upon their reaction rates by manipulating steric features of the chemical constructs. While replete with chemical structures and metabolic reactions throughout, the next section highlights all prodrug entries within the NMEs entering the US marketplace for the periods 2004–2008 and 2009–2017. Cataloged information relevant to this section is provided in two comprehensive appendices. The article concludes by conveying three case studies, which further serve to highlight the practical applications of prodrug design principles.