New aminoimidazoles as β-secretase (BACE-1) inhibitors showing amyloid-β (Aβ) lowering in brain.


Amino-2H-imidazoles are described as a new class of BACE-1 inhibitors for the treatment of Alzheimer's disease. Synthetic methods, crystal structures, and structure-activity relationships for target activity, permeability, and hERG activity are reported and discussed. Compound (S)-1m was one of the most promising compounds in this report, with high potency in the cellular assay and a good overall profile. When guinea pigs were treated with compound (S)-1m, a concentration and time dependent decrease in Aβ40 and Aβ42 levels in plasma, brain, and CSF was observed. The maximum reduction of brain Aβ was 40-50%, 1.5 h after oral dosing (100 μmol/kg). The results presented highlight the potential of this new class of BACE-1 inhibitors with good target potency and with low effect on hERG, in combination with a fair CNS exposure in vivo.

DOI: 10.1021/jm300991n
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@article{Gravenfors2012NewAA, title={New aminoimidazoles as β-secretase (BACE-1) inhibitors showing amyloid-β (Aβ) lowering in brain.}, author={Ylva Gravenfors and Jenny Viklund and Jan Blid and Tobias Ginman and Sofia Karlstr{\"{o}m and Jacob Kihlstr{\"{o}m and Karin Kolmodin and Johan Lindstr{\"{o}m and Stefan von Berg and Fredrik von Kieseritzky and Krisztian Bogar and Can Slivo and Britt-Marie Swahn and Lise-Lotte Olsson and Patrik Johansson and Susanna Eketj{\"a}ll and Johanna F{\"a}lting and Fredrik Jeppsson and Kia Str{\"{o}mberg and Juliette Janson and Fredrik Rahm}, journal={Journal of medicinal chemistry}, year={2012}, volume={55 21}, pages={9297-311} }