Automated flow systems for lead discovery and development

Synopsis

Lead discovery relies on the design and synthesis of new bioactive compounds that have the potential to become efficacious drugs. The process consists in the iterative generation of structure−ac=vity and structure-property relationship data resulting from the evaluation of hit analogues designed to improve potency, selectivity, in vivo efficacy and safety. Using traditional approaches, a significant time delay may occur from compound design to results, leading to slow and expensive hit-to-lead explorations. While the advent of computational tools and high-throughput screening has enabled the design, testing, and analysis of large number of compounds, the synthesis of compound collections is not as efficient and often represents an ongoing bottleneck in the process of drug discovery. In this context, flow chemistry and automation are considered valuable tools to solve limitations of chemical synthesis in terms of compound throughput, quality and scalability, and have shown great potential in uncovering and developing novel leads and drug candidates. In this communication, we report case studies where the use of automated flow-based systems was extremely helpful to expedite lead discovery and optimization. In particular, flow synthesizers, automation, process analytical technologies, and computational chemistry were integrated in a prototype system that contributes to the shortening of medicinal chemistry discovery cycles and to the process optimization of lead candidates and important biomarkers for druggable targets.