Discovery of a novel [3.2.1] benzo fused bicyclic sulfonamide-pyrazoles as potent, selective and efficacious γ-secretase inhibitors

Structure–activity relationship (SAR) of a novel, potent and metabolically stable series of benzo [3.2.1] bicyclic sulfonamide-pyrazoles as γ-secretase inhibitors are described. Compounds that are efficacious in reducing the cortical Aβx-40 levels in FVB mice via oral dose, as well as those with hig...

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Veröffentlicht in:	Bioorganic & medicinal chemistry letters 2013-02, Vol.23 (4), p.996-1000
Hauptverfasser:	Ye, Xiaocong M., Konradi, Andrei W., Sun, Minghua, Yuan, Shendong, Aubele, Danielle L., Dappen, Michael, Dressen, Darren, Garofalo, Albert W., Jagodzinski, Jacek J., Latimer, Lee, Probst, Gary D., Sham, Hing L., Wone, David, Xu, Ying-zi, Ness, Daniel, Brigham, Elizabeth, Kwong, Grace T., Willtis, Chris, Tonn, George, Goldbach, Erich, Quinn, Kevin P., Zhang, Hongbin H., Sauer, John-Michael, Bova, Michael, Basi, Guriqbal S.
Format:	Artikel
Sprache:	eng
Schlagworte:	Alzheimer’s disease Amyloid precursor protein Amyloid Precursor Protein Secretases - antagonists & inhibitors Amyloid Precursor Protein Secretases - metabolism Animals Bridged Bicyclo Compounds, Heterocyclic - chemistry Bridged Bicyclo Compounds, Heterocyclic - pharmacology Mice Notch proteinase inhibitors pyrazoles Pyrazoles - chemistry Pyrazoles - pharmacology Structure-Activity Relationship structure-activity relationships Sulfonamides - chemistry Sulfonamides - pharmacology γ-Secretase γ-Secretase inhibitor
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Beschreibung
Zusammenfassung:	Structure–activity relationship (SAR) of a novel, potent and metabolically stable series of benzo [3.2.1] bicyclic sulfonamide-pyrazoles as γ-secretase inhibitors are described. Compounds that are efficacious in reducing the cortical Aβx-40 levels in FVB mice via oral dose, as well as those with high selectivity over Notch, are highlighted.
ISSN:	0960-894X 1464-3405
DOI:	10.1016/j.bmcl.2012.12.039