Design, synthesis and structure-activity relationship of novel [3.3.1] bicyclic sulfonamide-pyrazoles as potent [gamma]-secretase inhibitors

The structure-activity relationship (SAR) of a novel, potent and metabolically stable series of sulfonamide-pyrazoles that attenuate [beta]-amyloid peptide synthesis via [gamma]-secretase inhibition is detailed herein. Sulfonamide-pyrazoles that are efficacious in reducing the cortical A[beta]x-40 l...

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Published inBioorganic & medicinal chemistry letters Vol. 21; no. 19; pp. 5791 - 5794
Main Authors Aubele, Danielle L, Truong, Anh P, Dressen, Darren B, Probst, Gary D, Bowers, Simeon, Mattson, Matthew N, Semko, Chris M, Sun, Minghua, Garofalo, Albert W, Konradi, Andrei W, Sham, Hing L, Zmolek, Wes, Wong, Karina, Goldbach, Erich, Quinn, Kevin P, Sauer, John-Michael, Brigham, Elizabeth F, Wallace, William, Nguyen, Lan, Bova, Michael P, Hemphill, Susanna S, Basi, Guriqbal
Format Journal Article
LanguageEnglish
Published 01.10.2011
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Abstract The structure-activity relationship (SAR) of a novel, potent and metabolically stable series of sulfonamide-pyrazoles that attenuate [beta]-amyloid peptide synthesis via [gamma]-secretase inhibition is detailed herein. Sulfonamide-pyrazoles that are efficacious in reducing the cortical A[beta]x-40 levels in FVB mice via a single PO dose, as well as sulfonamide-pyrazoles that exhibit selectivity for inhibition of APP versus Notch processing by [gamma]-secretase, are highlighted.
AbstractList The structure-activity relationship (SAR) of a novel, potent and metabolically stable series of sulfonamide-pyrazoles that attenuate [beta]-amyloid peptide synthesis via [gamma]-secretase inhibition is detailed herein. Sulfonamide-pyrazoles that are efficacious in reducing the cortical A[beta]x-40 levels in FVB mice via a single PO dose, as well as sulfonamide-pyrazoles that exhibit selectivity for inhibition of APP versus Notch processing by [gamma]-secretase, are highlighted.
Author Sauer, John-Michael
Probst, Gary D
Zmolek, Wes
Basi, Guriqbal
Wong, Karina
Dressen, Darren B
Nguyen, Lan
Truong, Anh P
Bowers, Simeon
Bova, Michael P
Konradi, Andrei W
Sham, Hing L
Hemphill, Susanna S
Garofalo, Albert W
Wallace, William
Semko, Chris M
Mattson, Matthew N
Goldbach, Erich
Aubele, Danielle L
Quinn, Kevin P
Brigham, Elizabeth F
Sun, Minghua
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Title Design, synthesis and structure-activity relationship of novel [3.3.1] bicyclic sulfonamide-pyrazoles as potent [gamma]-secretase inhibitors
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