Important Compound Classes
Title
Triazolo-azepine derivatives
Patent Application Number
WO 2019/121434 A1
Publication Date
June 27th, 2019
Priority Application
EP 17208057.4
Priority Date
December 18th, 2017
Inventors
Bartels, B.; Cook, X. A. F.; Ratni, H.; Reutlinger, M.; Vifian, W.
Assignee Company
Hoffmann-La Roche
Disease Area
Alzheimer’s disease, cerebral amyloid angiopathy, hereditary cerebral hemorrhage with amyloidosis, Dutch-type (HCHWA-D), multi-infarct dementia, dementia pugilistica, and Down syndrome.
Biological Target
γ-Secretase
Summary
The progressive neurodegenerative disorder known as Alzheimer’s disease was first described by the German psychiatrist Alois Alzheimer in 1907. According to the Alzheimer’s Association, in 2019 there were over 5 million Alzheimer’s disease patients in the U.S. alone, and this number is expected to increase to 16 million by 2050. The cost of care for patients in the U.S. is expected to exceed $290 billion in 2019 and rise to over $1.1 trillion by 2050 (https://www.alz.org/alzheimers-dementia/facts-figures). To date, the underlying cause of this condition remains unclear, and there are no therapies capable of arresting disease progression.
β-Amyloid plaques and neurofibrillary tangles in the cortical and subcortical regions of the brain have been linked to Alzheimer’s disease and numerous research teams have focused on the identification of compounds capable of preventing the development of these features. The formation of β-amyloid plaques begins when the amyloid precursor protein (APP) is cleaved by β-secretase 1 (BACE1) to produce two fragments, the soluble protein β-APP, and a membrane bound fragment designated C-99. Further processing of C-99 by γ-secretase produces a peptide fragment, Aβ42, which aggregates and becomes the main component of β-amyloid plaques. It has been hypothesized that inhibition of γ-secretase would prevent the formation of β-amyloid plaques and arrest progression of Alzheimer’s disease. The present application discloses a series of compounds that inhibit γ-secretase and are potentially useful for the treatment of Alzheimer’s disease. The application further describes the use of the compounds for the treatment of other diseases associated with β-amyloid plaques such as cerebral amyloid angiopathy, hereditary cerebral hemorrhage with amyloidosis, Dutch-type (HCHWA-D), multi-infarct dementia, dementia pugilistica, and Down syndrome.
Definitions
Key Structures
Biological Assay
Inhibition of production of Aβ42 by human neuroglioma H4 cells overexpressing human APP695 with the Swedish double mutation (K595N/M596L) as measured with an AlphaLisa assay kit (Human Amyloid beta 1–42 Kit: catalog #AL203C, PerkinElmer).
Biological Data
Claims
15 Total claims
10 Composition of matter claims
4 Method of use claims
1 Process claim
Recent Review Articles
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1.
Xia W.γ-Secretase and its modulators: Twenty years and beyond. Neuroscience Letters 2019, 701, 162–169.
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2.
Johnson D. S.; Pettersson M.. γ-secretase modulators as Aβ42-lowering pharmacological agents to treat Alzheimer’s disease. Topics in Medicinal Chemistry 2017, 24, 87–118.
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3.
Gu K.; Li Q.; Lin H.; Zhu J.; Mo J.; He S.; Lu X.; Jiang X.; Sun H.. Gamma secretase inhibitors: a patent. Expert Opinion on Therapeutic Patents 2017, 27 ( (7), ), 851–866.
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4.
Bursavich M. G.; Harrison, Bryce A.; Blain J. F.. Gamma Secretase Modulators: New Alzheimer’s Drugs on the Horizon? Journal of Medicinal Chemistry 2016, 59 ( (16), ), 7389–7409.
The author declares no competing financial interest.