6726
C. Sund et al. / Bioorg. Med. Chem. Lett. 22 (2012) 6721–6727
Figure 3. X-ray structure of 6 (PDB 4EWO) bound to human BACE-1 (the flap outlined for clarity). 1.8 Å resolution.
2. Klafh, H.-W.; Staufenbiel, M.; Kornhuber, J.; Wiltfang, J. Brain 2006, 2840.
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sures achieved with inhibitor 6 were not sufficient to affect Ab40
levels in the brain. The relatively weak efficacy in vivo is probably
not due to excessive protein binding (free unbound in mouse
serum = 10%).
In summary, guided by the lead compounds 1 and 2, a series of
low molecular weight and in some cases potent BACE-1 inhibitors
(4–10) were synthesized. Different heteroatom combinations on
the prime side core template, consisting of either 4,5,6,7-tetrahyd-
robenzazoles or a 4,5,6,7-tetrahydropyridinoazole, were explored
with the aim of fine tuning the basicity of the molecules and there-
by influence their inhibitory activities and DMPK properties. Less
polar heteroaromatics as in the pyrazolo analogues 6, 7 and 9
seemed to be preferred for good BACE-1 inhibitory activity,
whereas the more polar oxazole 4 and imidazole 5b analogues
were less preferred. Oxidizing the 3-hydroxyl group of 7 to the
3-oxo function to give 10 led to a weakened potency in the enzyme
based assay and to abolition of potency in the cell based assay.
Selectivity over Cathepsin D and BACE-2 was poor for this series
of compounds. The stability of the compounds in HLM could be im-
proved compared to the lead compounds 1 and 2 whereas perme-
ability was lower probably due to Pgp affinity. Compound 6 was
dosed in vivo in mice and although the compound reached the
brain, the exposure achieved did not elicit any change in Ab40
levels.
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Chaffee, S. C.; Cheng, Y.; Croghan, M.; Graceffa, R.; Harried, S.; Hickman, D.;
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Acknowledgements
We wish to thank Ann-Louise Hagbjörk, Annelie Lindqvist,
Veronica Werlinder, for excellent technical work in carrying out
HLM, Caco-2 and MDCK assays. Dr. Tatiana Agback and Dr. Kurt
Benkestock for excellent NMR and LCMS elucidations respectively
of the final compounds 1, 2, 4–10. We specially thank Prof. Dr. Ber-
til Samuelsson for initial revisions of this manuscript.
References and notes
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