Overview of strategies for addressing BRIs in drug discovery: Impact on optimization and design

While the process of generation of reactive metabolite data has become more straightforward, the conversion of that data into an optimization paradigm remains challenging. Recent studies have shown a very loose correlation between extent of reactive metabolite formation and observed toxicity, so setting stringent criteria likely leads to discarding compounds that would not have problems. On the other hand, the central role of reactive metabolites in most accepted mechanisms of drug-induced toxicity points to the fact that there is value in minimizing the property. Decision making based on information on reactive metabolite formation remains a difficult process in all phases of drug discovery and development. Decisions on compounds in discovery can be made based on a fixed threshold value or relative to a reference point within a chemical series, but should be made with a firm understanding of the limitation of the data.