Cyclopropyl-Fused 1,3-Thiazepines as BACE1 and BACE2 Inhibitors

摘要

Alzheimer's disease, the most common form of dementia, was originally described by German psychiatrist and neuropathologist Alois Alzheimer in 1906. Although the majority of cases are diagnosed in patients over 65, early onset Alzheimer's disease can occur much earlier. In 2010, there were over 35.6 million patients suffering from this disease, and it has been predicted that Alzheimer's disease will affect 1 in 85 people by 2050. Although the cause of Alzheimer's disease is unknown, disease progression has been linked to the formation of neurotoxic amyloid β peptides (Aβ1-40, Aβ1-42) in critical parts of the brain, which are produced as a result of the action of β-secretase (BACE1) on Aβ amyloid precursor protein (APP). BACE1 cleaves APP at the β-cleavage site, and further processing by γ-secretase generates the insoluble Aβ proteins, which in turn form oligomers and, ultimately, the plaques that are the hallmark of Alzheimer's disease. It has been suggested that inhibition of BACE1 processing of APP will decrease Aβ production, providing therapeutic relief.