AZD-3043

In the present study, the SD concept is part of the more general recognition that drug design needs to fully integrate metabolic con-siderations from the very beginning as metabolites contribute significantly to the overall activity and toxicity profile of the original drug and focus not on improving activity alone, but on improving the activity/toxicity ratio.This is usually characterized by the therapeutic index, typically defined as the ratio between the half-maximal toxic and effec-tive doses: TI = TD50/ED50.These ideas are the main underlying principles of retrometabolic drug design, which incorporates both SD and chem. delivery system (CDS) design.For most drugs, several metabolites are formed following administration, and they can contribute significantly not just to the overall activity, but also to toxicity and side effects.This can lead to complex time-profiles as illustrated in Figure 1(a), which shows the case of a hypothetical drug D that is present together with its active, toxic, and inactive metabolites.In light of these, the SD approach, which provides general drug design strategies, has particular potential.Because it often starts from a known active structure and focuses on designing safer drugs by decreasing side effects and toxicity, the likelihood of success is increased, especially considering the perspective highlighted by Sir James Black: the most fruitful basis for the discovery of a new drug is to start with an old drug.