Discovery and Chemical Development of BI 1181181 MZ: A Bis-Spirocyclic BACE-1 Inhibitor for the Treatment of Alzheimer’s Disease

A doubly spirocyclic motif was identified using novel structure-based design technology, and SAR based on molecular modeling and pKa modulation as well as metabolite analysis led to the clinical candidate BI 1181181 MZ, a potent and selective BACE1 inhibitor for the treatment of Alzheimer’s disease. Process research addressed key safety and scalability issues in the medicinal chemistry route and led to the design of a robust synthesis that supported development work packages.