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

The structure–activity relationship (SAR) of a novel, potent and metabolically stable series of sulfonamide-pyrazoles that attenuate β-amyloid peptide synthesis via γ-secretase inhibition is detailed herein. Sulfonamide-pyrazoles that are efficacious in reducing the cortical Aβx-40 levels in FVB mic...

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Veröffentlicht in:	Bioorganic & medicinal chemistry letters 2011-10, Vol.21 (19), p.5791-5794
Hauptverfasser:	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:	Artikel
Sprache:	eng
Schlagworte:	Alzheimer’s disease Amyloid beta-Peptides - metabolism Amyloid beta-Protein Precursor - antagonists & inhibitors Amyloid Precursor Protein Secretases - antagonists & inhibitors Animals Biological and medical sciences Drug Design Drug Evaluation, Preclinical Enzyme Inhibitors - chemical synthesis Enzyme Inhibitors - chemistry Enzyme Inhibitors - pharmacology Heterocyclic Compounds, 3-Ring - chemical synthesis Heterocyclic Compounds, 3-Ring - chemistry Heterocyclic Compounds, 3-Ring - pharmacology Inhibitory Concentration 50 Medical sciences Mice Mice, Inbred Strains Neuropharmacology Pharmacology. Drug treatments proteinase inhibitors Psychoanaleptics: cns stimulant, antidepressant agent, nootropic agent, mood stabilizer Psychoanaleptics: cns stimulant, antidepressant agent, nootropic agent, mood stabilizer..., (alzheimer disease) Psychology. Psychoanalysis. Psychiatry Psychopharmacology pyrazoles Structure-Activity Relationship structure-activity relationships Sulfonamide sulfonamides Sulfonamides - chemical synthesis Sulfonamides - chemistry Sulfonamides - pharmacology γ-Secretase inhibitor
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Zusammenfassung:	The structure–activity relationship (SAR) of a novel, potent and metabolically stable series of sulfonamide-pyrazoles that attenuate β-amyloid peptide synthesis via γ-secretase inhibition is detailed herein. Sulfonamide-pyrazoles that are efficacious in reducing the cortical Aβx-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 γ-secretase, are highlighted.
ISSN:	0960-894X 1464-3405
DOI:	10.1016/j.bmcl.2011.08.008