begacestat and Disease-Models--Animal

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.

Topics: Alzheimer Disease; Amyloid beta-Peptides; Amyloid Precursor Protein Secretases; Animals; Crystallography, X-Ray; Disease Models, Animal; Dose-Response Relationship, Drug; Drug Discovery; Enzyme Inhibitors; Mice; Mice, Transgenic; Models, Molecular; Molecular Conformation; Receptor, Notch1; Stereoisomerism; Structure-Activity Relationship; Sulfonamides; Thiophenes