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.

/pdf/future-therapeutics-in-alzheimer-s-disease-development-3i6nyndqz8.pdf

Future Therapeutics in Alzheimer's Disease: Development Status of BACE Inhibitors.

Background: Protein-protein interactions are a principal regulatory mechanism in biology, but also a common source of pathogenesis. Many proteins are susceptible to misfolding and amyloidogenesis, leading to human disease via a gain of pathogenic function. The assembly of these misfolded proteins into a variety of aggregates is linked to numerous debilitating diseases such as neurodegenerative diseases, polyneuropathies and cardiomyopathies. Recent studies from three diverse disciplines, neuropathology, genetics, and biophysics, have indicated a novel target for therapeutic intervention: ordered protein aggregation. However, previous small molecule based approaches to inhibit protein-protein interactions, particularly aggregating proteins, have had limited success, and subsequently inhibition of protein-protein interactions remains the \"Holy Grail\" of drug design. Methods: A few years ago we developed a new strategy that combines emerging chemical and biological technologies to address this problem. This strategy enables small molecules to recruit the steric bulk provided by the chaperone FKBP to the aggregating peptide and to thus effectively block the formation of pathogenic protein aggregates. Results: We have now expanded on this approach and have designed bifunctional small molecules that are able to recruit other cellular proteins that have been shown to modulate A-beta aggregation and to genetically interact with the A-beta aggregation pathway. To identify novel compounds that bind to different aggregation species of A-beta, we have used both rational design as well as an unbiased high throughput screening (HTS) approach, which we complement with computational scaffold hopping to identify structural analogs of hits. Conclusions: In addition to their potential as a starting point for the development of novel therapeutic agents for AD, these bifunctional small molecules can also be used as chemical probes to address unanswered questions regarding the molecular mechanisms underlying the pathogenesis of AD.

BACE1 is not the rate-limiting enzyme in Aβ production in the brains of APPswe transgenic mice: Pharmacological characterization of BACE1 using novel brain penetrant inhibitors.

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BACE1 is not the rate-limiting enzyme in Aβ production in the brains of APPswe transgenic mice: Pharmacological characterization of BACE1 using novel brain penetrant inhibitors.