Towards the Optimal Screening Collection: A Synthesis Strategy

Abstract

The development of effective small‐molecule probes and drugs entails at least three stages: 1) a discovery phase, often requiring the synthesis and screening of candidate compounds, 2) an optimization phase, requiring the synthesis and analysis of structural variants, 3) and a manufacturing phase, requiring the efficient, large‐scale synthesis of the optimized probe or drug. Specialized project groups tend to undertake the individual activities without prior coordination; for example, contracted (outsourced) chemists may perform the first activity while in‐house medicinal and process chemists perform the second and third development stages, respectively. The coordinated planning of these activities in advance of the first small‐molecule screen tends not to be undertaken, and each project group can encounter a bottleneck that could, in principle, have been avoided with advance planning. Therefore, a challenge for synthetic chemistry is to develop a new kind of chemistry that yields a screening collection comprising small molecules that increase the probability of success in all three phases. Although this transformative chemistry remains elusive, progress is being made. Herein, we review a newly emerging strategy in diversity‐oriented small‐molecule synthesis that may have the potential to achieve these challenging goals.