Article ; Online: Future Therapeutics in Alzheimer's Disease: Development Status of BACE Inhibitors.
BioDrugs : clinical immunotherapeutics, biopharmaceuticals and gene therapy
2016 Volume 30, Issue 3, Page(s) 173–194
Abstract: Alzheimer's disease (AD) is the primary cause of dementia in the elderly. It remains incurable and poses a huge socio-economic challenge for developed countries with an aging population. AD manifests by progressive decline in cognitive functions and ... ...
| Abstract | Alzheimer's disease (AD) is the primary cause of dementia in the elderly. It remains incurable and poses a huge socio-economic challenge for developed countries with an aging population. AD manifests by progressive decline in cognitive functions and alterations in behaviour, which are the result of the extensive degeneration of brain neurons. The AD pathogenic mechanism involves the accumulation of amyloid beta peptide (Aβ), an aggregating protein fragment that self-associates to form neurotoxic fibrils that trigger a cascade of cellular events leading to neuronal injury and death. Researchers from academia and the pharmaceutical industry have pursued a rational approach to AD drug discovery and targeted the amyloid cascade. Schemes have been devised to prevent the overproduction and accumulation of Aβ in the brain. The extensive efforts of the past 20 years have been translated into bringing new drugs to advanced clinical trials. The most progressed mechanism-based therapies to date consist of immunological interventions to clear Aβ oligomers, and pharmacological drugs to inhibit the secretase enzymes that produce Aβ, namely β-site amyloid precursor-cleaving enzyme (BACE) and γ-secretase. After giving an update on the development and current status of new AD therapeutics, this review will focus on BACE inhibitors and, in particular, will discuss the prospects of verubecestat (MK-8931), which has reached phase III clinical trials. |
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| MeSH term(s) | Alzheimer Disease/drug therapy ; Alzheimer Disease/metabolism ; Alzheimer Disease/physiopathology ; Amyloid Precursor Protein Secretases/antagonists & inhibitors ; Amyloid Precursor Protein Secretases/metabolism ; Amyloid beta-Peptides/metabolism ; Cyclic S-Oxides/pharmacology ; Enzyme Inhibitors/pharmacology ; Enzyme Inhibitors/therapeutic use ; Humans ; Imidazoles/pharmacology ; Immunization, Passive ; Immunotherapy/methods ; Molecular Targeted Therapy ; Peptidomimetics ; Small Molecule Libraries/pharmacology ; Spiro Compounds/pharmacology ; Thiadiazines/pharmacology ; Vaccination |
| Chemical Substances | Amyloid beta-Peptides ; Cyclic S-Oxides ; Enzyme Inhibitors ; Imidazoles ; Peptidomimetics ; Small Molecule Libraries ; Spiro Compounds ; Thiadiazines ; Amyloid Precursor Protein Secretases (EC 3.4.-) ; verubecestat (J1I0P6WT7T) ; lanabecestat (X8SPJ492VF) |
| Language | English |
| Publishing date | 2016-03-14 |
| Publishing country | New Zealand |
| Document type | Journal Article ; Review |
| ZDB-ID | 1364202-9 |
| ISSN | 1179-190X ; 1173-8804 |
| ISSN (online) | 1179-190X |
| ISSN | 1173-8804 |
| DOI | 10.1007/s40259-016-0168-3 |
| Database | MEDical Literature Analysis and Retrieval System OnLINE |
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