Employing Late-Stage Functionalization Strategies to Address Metabolic Challenges in Drug Discovery

In the course of medicinal chemistry campaigns, issues related to drug metabolism frequently present significant challenges to progressing chemical series towards tool molecules or clinical candidates. Addressing these issues typically requires designing molecules with specific point-changes to test particular metabolism-related hypotheses. However, accessing these test molecules in a timely manner to inform future rounds of decision-making and design often presents a significant synthetic challenge. In this report, we present case studies showcasing the use of Minsici and direct metalation chemistries as part of a Late-Stage Functionalization strategy to address specific metabolic issues plaguing two medicinal chemistry programs. The success of these approaches allowed rapid access to new analogs with improved metabolic stability, and more importantly, key insights that informed on strategies to progress these chemical series towards valuable tool compounds.