Evolution of Synthetic Strategies for Lilly’s Clinical BACE Inhibitors: From Discovery Concepts to Manufacturing-Ready Routes

Alzheimer’s disease (AD) remains a critical unmet medical need that Eli Lilly and Company has been working to address for many years. This manuscript details the evolution of Lilly’s BACE inhibitor program, highlighting the iterative synthetic strategies that enabled the advancement of multiple clinical development candidates. The work underscores how strategic retrosynthetic analysis and process optimization facilitated the translation of intricate medicinal chemistry targets into robust manufacturing processes, ultimately supporting clinical development efforts in AD despite the inherent challenges and program terminations encountered along the way.