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Pure Appl. Chem., 2008, Vol. 80, No. 8, pp. 1669-1682

Retrometabolic drug design: Principles and recent developments

Nicholas Bodor1 and Peter Buchwald2

1 Center for Drug Discovery, University of Florida, Health Science Center, P.O. Box 100497, Gainesville, FL 32610, USA
2 Molecular and Cellular Pharmacology and Diabetes Research Institute, University of Miami, Miami, FL 33136, USA

Abstract: Retrometabolic drug design incorporates two major systematic approaches: the design of soft drugs (SDs) and of chemical delivery systems (CDSs). Both aim to design new, safe drugs with an improved therapeutic index by integrating structure-activity and -metabolism relationships; however, they achieve it by different means: whereas SDs are new, active therapeutic agents that undergo predictable metabolism to inactive metabolites after exerting their desired therapeutic effect, CDSs are biologically inert molecules that provide enhanced and targeted delivery of an active drug to a particular organ or site through a designed sequential metabolism that involves several steps. General principles and recent developments are briefly reviewed with various illustrative examples from different therapeutic areas with special focus on soft corticosteroids and on brain targeting.