Discovery of a novel series of Notch-sparing γ-secretase inhibitors

Lead optimization studies of Notch-sparing GSI 2a led to the discovery of analog 8e with improved γ-secretase inhibitory potency and Notch-sparing selectivity. Using a cell-based assay, we have identified a new series of Notch-sparing γ-secretase inhibitors from HTS screening leads 2a and 2e. Lead o...

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Veröffentlicht in:	Bioorganic & medicinal chemistry 2008-07, Vol.18 (14), p.4232-4236
Hauptverfasser:	Kreft, Anthony, Harrison, Boyd, Aschmies, Suzan, Atchison, Kevin, Casebier, David, Cole, Derek C., Diamantidis, George, Ellingboe, John, Hauze, Diane, Hu, Yun, Huryn, Donna, Jin, Mei, Kubrak, Dennis, Lu, Peimin, Lundquist, Joseph, Mann, Charles, Martone, Robert, Moore, William, Oganesian, Aram, Porte, Alex, Riddell, Dave R., Sonnenberg-Reines, June, Stock, Joseph R., Sun, Shaiu-Ching, Wagner, Erik, Woller, Kevin, Xu, Zheng, Zhou, Hua, Steven Jacobsen, J.
Format:	Artikel
Sprache:	eng
Schlagworte:	Alzheimer Disease - drug therapy Alzheimer’s disease Amyloid Amyloid - chemistry Amyloid Precursor Protein Secretases - antagonists & inhibitors Amyloid Precursor Protein Secretases - chemistry Biological and medical sciences Carbon - chemistry Chemistry, Pharmaceutical - methods Drug Design Drug Evaluation, Preclinical Enzyme Inhibitors - chemical synthesis Enzyme Inhibitors - pharmacology Humans Medical sciences Models, Chemical Neuropharmacology Notch Pharmacology. Drug treatments Protease inhibitor Psychoanaleptics: cns stimulant, antidepressant agent, nootropic agent, mood stabilizer Psychoanaleptics: cns stimulant, antidepressant agent, nootropic agent, mood stabilizer..., (alzheimer disease) Psychology. Psychoanalysis. Psychiatry Psychopharmacology Receptors, Notch - antagonists & inhibitors Receptors, Notch - metabolism Structure-Activity Relationship γ-Secretase
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Zusammenfassung:	Lead optimization studies of Notch-sparing GSI 2a led to the discovery of analog 8e with improved γ-secretase inhibitory potency and Notch-sparing selectivity. Using a cell-based assay, we have identified a new series of Notch-sparing γ-secretase inhibitors from HTS screening leads 2a and 2e. Lead optimization studies led to the discovery of analog 8e with improved γ-secretase inhibitory potency and Notch-sparing selectivity.
ISSN:	0960-894X 0968-0896 1464-3405 1464-3391
DOI:	10.1016/j.bmcl.2008.05.064