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

@article{Stamford2012DiscoveryOA,
  title={Discovery of an Orally Available, Brain Penetrant BACE1 Inhibitor that Affords Robust CNS Aβ Reduction.},
  author={Andrew W. Stamford and Jack D Scott and Sarah W. Li and Sachidananda Babu and Dawit G. Tadesse and Rachael Hunter and Yusheng Wu and Jeffrey Misiaszek and Jared Cumming and Eric Gilbert and Chunli Huang and B Mckittrick and Liwu Hong and Tao Guo and Zhaoning Zhu and Corey O Strickland and Peter Orth and Johannes H. Voigt and Matthew E. Kennedy and Xia Chen and Reshma Kuvelkar and Robert A. Hodgson and Lynn A. Hyde and Kathleen B Cox and Leonard V. Favreau and Eric M. Parker and William J. Greenlee},
  journal={ACS medicinal chemistry letters},
  year={2012},
  volume={3 11},
  pages={897-902}
}
Inhibition of BACE1 to prevent brain Aβ 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 Aβ 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… CONTINUE READING

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