Targeting the BACE1 Active Site Flap Leads to a Potent Inhibitor That Elicits Robust Brain Aβ Reduction in Rodents.

@article{Wu2016TargetingTB,
  title={Targeting the BACE1 Active Site Flap Leads to a Potent Inhibitor That Elicits Robust Brain Aβ Reduction in Rodents.},
  author={Yong-Jin Wu and Jason M Guernon and Fukang Yang and Lawrence B. Snyder and Jianliang Shi and Andrea Mcclure and Ramkumar Rajamani and Hyunsoo K Park and Alicia T Ng and Hal Lewis and Chiehying J Chang and Dan Camac and Jeremy H. Toyn and Michael K. Ahlijanian and Charles F. Albright and John E. Macor and Lorin A. Thompson},
  journal={ACS medicinal chemistry letters},
  year={2016},
  volume={7 3},
  pages={271-6}
}
By targeting the flap backbone of the BACE1 active site, we discovered 6-dimethylisoxazole-substituted biaryl aminothiazine 18 with 34-fold improved BACE1 inhibitory activity over the lead compound 1. The cocrystal structure of 18 bound to the active site indicated two hydrogen-bond interactions between the dimethylisoxazole and threonine 72 and glutamine 73 of the flap. Incorporation of the dimethylisoxazole substitution onto the related aminothiazine carboxamide series led to pyrazine… CONTINUE READING

References

Publications referenced by this paper.
Showing 1-10 of 19 references

BACE inhibitors. WO-2011/005738

  • J. E. Audia, D. J. Mergott, +4 authors L.L.
  • 2015

3 , 5Dimethylisoxazoles act as acetyllysinemimetic bromodomain ligands

  • D. S. Hewings, M. Wang, +9 authors T. D. Heightman
  • J . Med . Chem .
  • 2011

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