In the field of drug discovery, retrometabolic drug design is a strategy for the design of safer drugs either using predictable metabolism to an inactive moiety or using targeted drug delivery approaches. The phrase retrometabolic drug design was coined by Nicholas Bodor. The method is analogous to retrosynthetic analysis where the synthesis of a target molecule is planned backwards. In retrometabolic drug design, metabolic reaction information of drugs is used to design parent drugs whose metabolism and distribution can be controlled to target and eliminate the drug to increase efficacy and minimize undesirable side effects. The new drugs thus designed achieve selective organ and/or therapeutic site drug targeting and produce safe therapeutic agents and safe environmental chemicals. These approaches represent systematic methodologies that thoroughly integrate structure-activity (SAR) and structure-metabolism (SMR) relationships and are aimed at designing safe, locally active compounds 

The retrometabolic drug design encompasses two distinct approaches. One approach is the design of soft drugs (SDs), new, active therapeutic agents, often isosteric or isolelectronic analogs of a lead compound, with a chemical structure specifically designed to allow predictable metabolism into inactive metabolites after exerting their desired therapeutic effect(s). The other approach is the design of chemical delivery systems (CDSs) CDSs are biologically inert molecules intended to enhance drug delivery to a particular organ or site and requiring several conversion steps before releasing the active drug.

Although both retrometabolic design approaches involve chemical modifications of the molecular structure and both require enzymatic reactions to fulfill drug targeting, the principles of SD and CDS design are distinctly different. While CDSs are inactive as administered and sequential enzymatic reactions provide the differential distribution and ultimately release the active drug, SDs are active as administered and are designed to be easily metabolized into inactive species. Assuming an ideal situation, with a CDS the drug is present at the site and nowhere else in the body because enzymatic processes destroy the drug at those sites. Whereas, CDSs are designed to achieve drug targeting at a selected organ or site, SDs was designed to afford a differential distribution that can be regarded as reverse targeting.

These retrometabolic design strategies were introduced by Nicholas Bodor, one of the first and most prominent advocates for the early integration of metabolism, pharmacokinetic and general physicochemical considerations in the drug design process. These drug design concepts recognize the importance of design-controlled metabolism and directly focus not on the increase of activity alone but on the increase of the activity/toxicity ratio therapeutic index in order to deliver the maximum benefit while also reducing or eliminating unwanted side effects. The importance of this field is reviewed in a book dedicated to the subject  was well as by a full of Burger's Medicinal Chemistry and Drug Design, with close to 150 chemical structures and more than 450 references. At the time of its introduction, the idea of designed-in metabolism represented a significant novelty and was against mainstream thinking then in place that instead focused on minimizing or entirely eliminating drug metabolism.

Best Regards,
Nancy Ella
Associate Managing Editor
Drug Designing: Open Access