1. Design, synthesis and structure-activity relationship of novel [3.3.1] bicyclic sulfonamide-pyrazoles as potent γ-secretase inhibitors.
- Author
-
Aubele DL, Truong AP, Dressen DB, Probst GD, Bowers S, Mattson MN, Semko CM, Sun M, Garofalo AW, Konradi AW, Sham HL, Zmolek W, Wong K, Goldbach E, Quinn KP, Sauer JM, Brigham EF, Wallace W, Nguyen L, Bova MP, Hemphill SS, and Basi G
- Subjects
- Amyloid beta-Peptides metabolism, Animals, Drug Evaluation, Preclinical, Enzyme Inhibitors chemistry, Heterocyclic Compounds, 3-Ring chemistry, Inhibitory Concentration 50, Mice, Mice, Inbred Strains, Structure-Activity Relationship, Sulfonamides chemistry, Amyloid Precursor Protein Secretases antagonists & inhibitors, Amyloid beta-Protein Precursor antagonists & inhibitors, Drug Design, Enzyme Inhibitors chemical synthesis, Enzyme Inhibitors pharmacology, Heterocyclic Compounds, 3-Ring chemical synthesis, Heterocyclic Compounds, 3-Ring pharmacology, Sulfonamides chemical synthesis, Sulfonamides pharmacology
- Abstract
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., (Copyright © 2011 Elsevier Ltd. All rights reserved.)
- Published
- 2011
- Full Text
- View/download PDF