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Review
. 2024 May;23(5):365-380.
doi: 10.1038/s41573-024-00914-7. Epub 2024 Apr 2.

The landscape of small-molecule prodrugs

Zachary Fralish  1 , Ashley Chen  2 , Shaharyar Khan  3 , Pei Zhou  4 , Daniel Reker  5
Affiliations
Review

The landscape of small-molecule prodrugs

Zachary Fralish et al. Nat Rev Drug Discov. 2024 May.

Abstract

Prodrugs are derivatives with superior properties compared with the parent active pharmaceutical ingredient (API), which undergo biotransformation after administration to generate the API in situ. Although sharing this general characteristic, prodrugs encompass a wide range of different chemical structures, therapeutic indications and properties. Here we provide the first holistic analysis of the current landscape of approved prodrugs using cheminformatics and data science approaches to reveal trends in prodrug development. We highlight rationales that underlie prodrug design, their indications, mechanisms of API release, the chemistry of promoieties added to APIs to form prodrugs and the market impact of prodrugs. On the basis of this analysis, we discuss strengths and limitations of current prodrug approaches and suggest areas for future development.

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