Aminoimidazoles as BACE-1 inhibitors: the challenge to achieve in vivo brain efficacy.

  title={Aminoimidazoles as BACE-1 inhibitors: the challenge to achieve in vivo brain efficacy.},
  author={Britt-Marie Swahn and J{\"o}rg Holenz and Jacob Kihlstr{\"o}m and Karin Kolmodin and Johan Lindstr{\"o}m and Niklas Plobeck and Didier Rotticci and Fernando W Sehgelmeble and Marie Sundstr{\"o}m and Stefan von Berg and Johanna M F{\"a}lting and Biljana Georgievska and Susanne Gustavsson and Jan A. M. Neelissen and Margareta Ek and L Olsson},
  journal={Bioorganic & medicinal chemistry letters},
  volume={22 5},
The evaluation of a series of bicyclic aminoimidazoles as potent BACE-1 inhibitors is described. The crystal structures of compounds 14 and 23 in complex with BACE-1 reveal hydrogen bond interactions with the protein important for achieving potent inhibition. The optimization of permeability and efflux properties of the compounds is discussed as well as the importance of these properties for attaining in vivo brain efficacy. Compound (R)-25 was selected for evaluation in vivo in wild type mice… CONTINUE READING
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