Affiliation:
1. Department of Toxicology and Military Pharmacy, Faculty of Military Health Sciences, University of Defence in Brno, Hradec Kralove, Czech Republic
2. Biomedical Research Center, University Hospital Hradec Kralove, Hradec Kralove, Czech Republic
Abstract
:
β-secretase (BACE1) has been regarded as a prime target for the development of amyloid
beta (Aβ) lowering drugs in the therapy of Alzheimer´s disease (AD). Although the enzyme was
discovered in 1991 and helped to formulate the Aβ hypothesis as one of the very important features
of AD etiopathogenesis, progress in AD treatment utilizing BACE1 inhibitors has remained limited.
Moreover, in the last years, major pharmaceutical companies have discontinued clinical trials of
five BACE1 inhibitors that had been strongly perceived as prospective. In our review, the Aβ hypothesis,
the enzyme, its functions, and selected substrates are described. BACE1 inhibitors are
classified into four generations. Those that underwent clinical trials displayed adverse effects, including
weight loss, skin rashes, worsening of neuropsychiatric symptoms, etc. Some inhibitors
could not establish a statistically significant risk-benefit ratio, or even scored worse than placebo.
We still believe that drugs targeting BACE1 may still hide some potential, but a different approach
to BACE1 inhibition or a shift of focus to modulation of its trafficking and/or post-translational
modification should now be followed.
Publisher
Bentham Science Publishers Ltd.
Subject
Pharmacology (medical),Psychiatry and Mental health,Clinical Neurology,Neurology,Pharmacology,General Medicine
Cited by
14 articles.
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