Discovery of an Orally Available, Brain Penetrant BACE1 Inhibitor That Affords Robust CNS Aβ Reduction

Inhibition of BACE1 to prevent brain A beta peptide formation is a potential disease modifying approach to the treatment of Alzheimer's disease. Despite over a decade of drug discovery efforts, the identification of brain penetrant BACE1 inhibitors that substantially lower CNS A beta levels following systemic administration remains challenging. In this report we describe structure-based optimization of a series of brain-penetrant BACE1 inhibitors derived from an iminopyrimidinone scaffold. Application of structure-based design in tandem with control of physicochemical properties culminated in the discovery of compound 16, which potently reduced cortex and CSF A beta 40 levels when administered orally to rats.