Inhibition of BACE1 to prevent brain A尾 peptide formation is a potential disease-modifying approach to the treatment of Alzheimer鈥檚 disease. Despite over a decade of drug discovery efforts, the identification of brain-penetrant BACE1 inhibitors that substantially lower CNS A尾 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尾40 levels when administered orally to rats.
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