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A Potent and Orally Efficacious, Hydroxyethylamine-Based Inhibitor of ?-Secretase.

ABSTRACT: ?-Secretase inhibitors are potentially disease-modifying treatments for Alzheimer's disease. Previous efforts in our laboratory have resulted in hydroxyethylamine-derived inhibitors such as 1 with low nanomolar potency against ?-site amyloid precursor protein cleaving enzyme (BACE). When dosed intravenously, compound 1 was also shown to significantly reduce A?40 levels in plasma, brain, and cerebral spinal fluid. Herein, we report further optimizations that led to the discovery of inhibitor 16 as a novel, potent, and orally efficacious BACE inhibitor.

SUBMITTER: Kaller MR 

PROVIDER: S-EPMC4025811 | biostudies-other | 2012 Nov

REPOSITORIES: biostudies-other

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A Potent and Orally Efficacious, Hydroxyethylamine-Based Inhibitor of β-Secretase.

Kaller Matthew R MR   Harried Scott S SS   Albrecht Brian B   Amarante Patricia P   Babu-Khan Safura S   Bartberger Michael D MD   Brown James J   Brown Ryan R   Chen Kui K   Cheng Yuan Y   Citron Martin M   Croghan Michael D MD   Graceffa Russell R   Hickman Dean D   Judd Ted T   Kriemen Chuck C   La Daniel D   Li Vivian V   Lopez Patricia P   Luo Yi Y   Masse Craig C   Monenschein Holger H   Nguyen Thomas T   Pennington Lewis D LD   Miguel Tisha San TS   Sickmier E Allen EA   Wahl Robert C RC   Weiss Matthew M MM   Wen Paul H PH   Williamson Toni T   Wood Stephen S   Xue May M   Yang Bryant B   Zhang Jianhua J   Patel Vinod V   Zhong Wenge W   Hitchcock Stephen S  

ACS medicinal chemistry letters 20120329 11

β-Secretase inhibitors are potentially disease-modifying treatments for Alzheimer's disease. Previous efforts in our laboratory have resulted in hydroxyethylamine-derived inhibitors such as 1 with low nanomolar potency against β-site amyloid precursor protein cleaving enzyme (BACE). When dosed intravenously, compound 1 was also shown to significantly reduce Aβ40 levels in plasma, brain, and cerebral spinal fluid. Herein, we report further optimizations that led to the discovery of inhibitor 16 a  ...[more]

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