Potential novel targets for Alzheimer pharmacotherapy: II. Update on secretase inhibitors and related approaches

@article{Mikulca2014PotentialNT,
  title={Potential novel targets for Alzheimer pharmacotherapy: II. Update on secretase inhibitors and related approaches},
  author={J. A. Mikulca and V Nguyen and David A Gajdosik and Samerawit Teklu and E. A. Giunta and E. A. Lessa and Cp. Tran and E. C. Terak and R. B. Raffa},
  journal={Journal of Clinical Pharmacy and Therapeutics},
  year={2014},
  volume={39}
}
The prevailing theory regarding Alzheimer disease (AD) is that insoluble amyloid β‐peptide (Aβ) plays a critical role in the cortical plaques characteristic of the disease. Because Aβ is formed from the sequential splicing of amyloid precursor protein (APP) catalysed by ‘secretase’ enzymes (α, β and γ), clinical trials of secretase inhibitors will either result in beneficial pharmacotherapy or, if negative, cast doubt on the role of Aβ in AD. With recent clinical trial failures, is the A… 
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References

SHOWING 1-10 OF 68 REFERENCES

Potential novel targets for Alzheimer pharmacotherapy: I. Secretases

The clinical trials of compounds designed and in various stages of development will result in drugs with dramatically better clinical efficacy or, if negative, will force a reassessment of the theory about the role of Aβ in AD.

γ-Secretase Inhibitors for Alzheimer’s Disease

The results of studies to date suggest that γ-secretase inhibitors have the potential to address a large unmet medical need if the technical challenges can be overcome, and biomarkers for efficacy and toxicity would be helpful in clinical trials.

Gamma-secretase inhibitors for Alzheimer's disease: balancing efficacy and toxicity.

The results of studies to date suggest that gamma-secretase inhibitors have the potential to address a large unmet medical need if the technical challenges can be overcome, and biomarkers for efficacy and toxicity would be helpful in clinical trials.

Robust Central Reduction of Amyloid-β in Humans with an Orally Available, Non-Peptidic β-Secretase Inhibitor

The magnitude and duration of central Aβ reduction obtainable with BACE1 inhibition positions this protease as a tractable small-molecule target through which to test the amyloid hypothesis in man.

Gamma-secretase as a therapeutic target for the treatment of Alzheimer's disease.

This review describes the literature regarding the discovery of the nature of gamma-secretase, the development of small molecule inhibitors and their in vivo profiles, and the effect of alternative, mechanism-based activities.

Immunotherapy for Alzheimer's disease.

Development of semagacestat (LY450139), a functional γ-secretase inhibitor, for the treatment of Alzheimer's disease

On the basis of extant data, semagacestat seems to be well tolerated, with most adverse events related to its actions on inhibition of peripheral Notch cleavage, and clinical efficacy has not been detectable because of the short duration of the current trials.

Identification of BACE2 as an avid ß-amyloid-degrading protease

Based on its high catalytic efficiency, its ability to degrade Aß intracellularly, and other characteristics, BACE2 represents a particulary strong therapeutic candidate for the treatment or prevention of AD.

Mice deficient in BACE1, the Alzheimer's β-secretase, have normal phenotype and abolished β-amyloid generation

These results provide validation of BACE1 as the major β-secretase in vivo and suggest that therapeutic inhibition of Bace1 for the treatment of Alzheimer's disease may be free of mechanism-based toxicity.

Plasma amyloid-β as a predictor of dementia and cognitive decline: a systematic review and meta-analysis.

Overall, the literature indicates that plasma Aβ(42):Aβ(40) ratios predict development of AD and dementia, however, significant heterogeneity in the meta-analysis underlines the need for substantial further investigation of plasma amyloid-β levels as a preclinical biomarker.
...