期刊
ACS MEDICINAL CHEMISTRY LETTERS
卷 3, 期 11, 页码 897-902出版社
AMER CHEMICAL SOC
DOI: 10.1021/ml3001165
关键词
BACE1; inhibitor; Alzheimer's disease; A beta 40; iminopyrimidinone; X-ray crystallography
资金
- National Science Foundation
- National Institutes of Health/National Institute of General Medical Sciences under NSF [DMR-0936384]
- National Institutes of Health, through National Institute of General Medical Sciences [GM103485]
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.
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