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Peer-reviewed veterinary case report

Discovery of begacestat, a Notch-1-sparing gamma-secretase inhibitor for the treatment of Alzheimer's disease.

Journal:
Journal of medicinal chemistry
Year:
2008
Authors:
Mayer, Scott C et al.
Affiliation:
Chemical and Screening Sciences · United States
Species:
rodent

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.

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Original publication: https://pubmed.ncbi.nlm.nih.gov/19012391/