Towards the Optimal Screening Collection: A Synthesis Strategy

Abstract

The development of effective small-molecule probes and drugs entails a discovery phase, often requiring the synthesis and screening of candidate compounds, an optimization phase requiring the synthesis and analysis of structural variants, and a manufacturing phase requiring the efficient, large-scale synthesis of the optimized probe or drug. In the pharmaceutical industry, the original chemistry team-based approach is evolving to a bucket brigade-based approach where, increasingly, contracted (outsourced) chemists perform the first activity while in-house medicinal and process chemists, respectively, perform the second and third activities. The up-front coordination of these activities tends not to be optimized – each has a life of its own and each can result in a bottleneck. Therefore, a challenge for the field of synthetic chemistry is to develop a new kind of chemistry that yields small molecules that increase the probability of success in all subsequent facets of the probe- and drug-discovery pipelines, including discovery, optimization and manufacturing. Whereas this transformative chemistry remains elusive, progress is being made. Here, we review a newly emerging strategy in diversity-oriented small-molecule synthesis that may have the potential to achieve these challenging goals in the future.