( S) -N-(5-Chlorothiophene-2-sulfonyl)-β,β-diethylalaninol a Notch-1-sparing γ-secretase inhibitor

Accumulation of beta-amyloid (Aβ), produced by the proteolytic cleavage of amyloid precursor protein (APP) by β- and γ-secretase, is widely believed to be associated with Alzheimer’s disease (AD). Research around the high-throughput screening hit ( S)-4-chlorophenylsulfonyl isoleucinol led to the id...

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Bibliographic Details
Published in:Bioorganic & medicinal chemistry letters 2009-02, Vol.19 (3), p.926-929
Main Authors: Cole, Derek C., Stock, Joseph R., Kreft, Anthony F., Antane, Madelene, Aschmies, Suzan H., Atchison, Kevin P., Casebier, David S., Comery, Thomas A., Diamantidis, George, Ellingboe, John W., Harrison, Boyd L., Hu, Yun, Jin, Mei, Kubrak, Dennis M., Lu, Peimin, Mann, Charles W., Martone, Robert L., Moore, William J., Oganesian, Aram, Riddell, David R., Sonnenberg-Reines, June, Sun, Shaiu-Ching, Wagner, Erik, Wang, Zheng, Woller, Kevin R., Xu, Zheng, Zhou, Hua, Jacobsen, J. Steven
Format: Article
Language:English
Subjects:
Alcohols
Alzheimer Disease - drug therapy
Alzheimer’s disease
Amyloid beta-Protein Precursor - chemistry
Amyloid Precursor Protein Secretases - antagonists & inhibitors
Amyloid Precursor Protein Secretases - metabolism
Animals
Biological and medical sciences
Drug Design
Humans
Isoleucine - analogs & derivatives
Isoleucine - chemistry
Medical sciences
Models, Chemical
Neuropharmacology
Pharmacology. Drug treatments
Propanolamines - chemistry
Psychoanaleptics: cns stimulant, antidepressant agent, nootropic agent, mood stabilizer
Psychoanaleptics: cns stimulant, antidepressant agent, nootropic agent, mood stabilizer..., (alzheimer disease)
Psychology. Psychoanalysis. Psychiatry
Psychopharmacology
Receptor, Notch1 - metabolism
Sulfonamide
Sulfonamides - chemistry
γ-Secretase inhibitor
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Summary:Accumulation of beta-amyloid (Aβ), produced by the proteolytic cleavage of amyloid precursor protein (APP) by β- and γ-secretase, is widely believed to be associated with Alzheimer’s disease (AD). Research around the high-throughput screening hit ( S)-4-chlorophenylsulfonyl isoleucinol led to the identification of the Notch-1-sparing (9.5-fold) γ-secretase inhibitor ( S)- N-(5-chlorothiophene-2-sulfonyl)-β,β-diethylalaninol 7.b.2 (Aβ 40/42 EC 50 = 28 nM), which is efficacious in reduction of Aβ production in vivo.
ISSN:0960-894X
1464-3405
DOI:10.1016/j.bmcl.2008.11.116