Important Compound Classes
Title
Triazolo pyridines as modulators of gamma secretase
Patent Application Number
WO 2019/121596 A1
Publication Date
June 27th, 2019
Priority Application
EP 17208420.4
Priority Date
December 19th, 2017
Inventors
Heine, N.; Eickmeier, C.; Gerlach, K.; Gross, U.
Assignee Company
Boehringer Ingelheim International
Disease Area
Alzheimer’s disease and Aβ42 related pathologies
Biological Target
γ-Secretase
Summary
In 1907, the German psychiatrist Alois Alzheimer described a patient suffering from a progressive neurodegenerative disorder that would eventually be designated Alzheimer’s disease. In the U.S., this debilitating condition afflicts over 5 million people, and the associated patient care cost is estimated to exceed $290 billion. These figures are expected to rise to over 16 million patients and $1.1 trillion in patient care costs by 2050 (https://www.alz.org/alzheimers-dementia/facts-figures). This disease has been a major focus of academic and industrial research teams across the globe, but despite these efforts there are no effective therapeutic agents, and the root cause Alzheimer’s disease remains a mystery.
Several lines of research have linked Alzheimer’s disease to the formation of β-amyloid plaques and neurofibrillary tangles in the cortical and subcortical regions of the brain. It has been further postulated that therapeutic agents capable of preventing the formations of these features could prevent or slow disease progression. β-Amyloid plaques are insoluble aggregates of the peptide Aβ42, which is in turn generated from the amyloid precursor protein (APP) via sequential processing by β-secretase 1 (BACE1) and γ-secretase. Initial cleavage of APP by BACE1 produces β-APP, a soluble peptide, and a membrane bound peptide designated C-99. Cleavage of C-99 by γ-secretase produces Aβ42, which aggregates to form β-amyloid plaques. Numerous research teams have focused on the identification of compounds capable of inhibiting either BACE-1 or γ-secretase in an effort to develop novel therapies for the treatment of Alzheimer’s disease. The present disclosure describes a series of novel [1,2,4]triazolo[1,5-a]pyridine and their use as therapies for the treatment of Aβ-related pathologies such as Alzheimer’s disease.
Definitions
Key Structures
Biological Assay
Inhibition of Aβ42 production by H4 neuroglioma cells stably expressing the human APP695 isoform as measured using an Aβ42 specific electrochemiluminescence assay provided by Mesa Scale Discovery (Catalog# L21CA-1).
Biological Data
Claims
7 Total claims
5 Composition of matter claims
2 Method of use claims
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.