Quality by Design in lead optimization: a new strategy to address productivity in drug discovery

The constant decline in drug discovery productivity despite the continuous growth in R&D investments has been on the table for many years and is driving changes in the current business model.We have focused our attention on what appears to be by far the major cause of attrition, the intrinsic quality of drug candidates; with the assumption that candidate quality can be designed and assessed at a rather early stage in drug discovery we have developed tools such as CNS chemical space mapping through PLS analysis, Drug Efficiency (DRUGeff) and the mechanistic PK/PD hypothesis. We also introduced best practices that were found extremely valuable which will be discussed in this article.

► High attrition has put the entire Pharma R&D business model under pressure. ► The selection of quality candidates is key to achieve efficiency and cost reduction. ► PLS analysis of in silico properties is a useful tool in the hit to lead phase. ► Drug Efficiency can help the prioritization of compounds in lead optimization. ► The mechanistic PK/PD hypothesis is key for dose selection in in vivo studies.