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Discovery of begacestat, a Notch-1-sparing gamma-secretase inhibitor for the treatment of Alzheimer's disease.
- Source :
-
Journal of medicinal chemistry [J Med Chem] 2008 Dec 11; Vol. 51 (23), pp. 7348-51. - Publication Year :
- 2008
-
Abstract
- SAR on HTS hits 1 and 2 led to the potent, Notch-1-sparing GSI 9, which lowered brain Abeta in Tg2576 mice at 100 mg/kg po. Converting the metabolically labile methyl groups in 9 to trifluoromethyl groups afforded the more stable analogue 10, which had improved in vivo potency. Further side chain modification afforded the potent Notch-1-sparing GSI begacestat (5), which was selected for development for the treatment of Alzheimer's disease.
- Subjects :
- Alzheimer Disease enzymology
Amyloid Precursor Protein Secretases metabolism
Amyloid beta-Peptides metabolism
Animals
Crystallography, X-Ray
Disease Models, Animal
Dose-Response Relationship, Drug
Enzyme Inhibitors chemical synthesis
Enzyme Inhibitors chemistry
Mice
Mice, Transgenic
Models, Molecular
Molecular Conformation
Stereoisomerism
Structure-Activity Relationship
Sulfonamides chemical synthesis
Sulfonamides chemistry
Thiophenes chemical synthesis
Thiophenes chemistry
Alzheimer Disease drug therapy
Amyloid Precursor Protein Secretases antagonists & inhibitors
Drug Discovery
Enzyme Inhibitors pharmacology
Receptor, Notch1 metabolism
Sulfonamides pharmacology
Thiophenes pharmacology
Subjects
Details
- Language :
- English
- ISSN :
- 1520-4804
- Volume :
- 51
- Issue :
- 23
- Database :
- MEDLINE
- Journal :
- Journal of medicinal chemistry
- Publication Type :
- Academic Journal
- Accession number :
- 19012391
- Full Text :
- https://doi.org/10.1021/jm801252w