کد مقاله | کد نشریه | سال انتشار | مقاله انگلیسی | نسخه تمام متن |
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1357563 | 981258 | 2016 | 15 صفحه PDF | دانلود رایگان |
γ-Secretase modulators (GSMs), which lower pathogenic amyloid beta (Aβ) without affecting the production of total Aβ or Notch signal, have emerged as a potential therapeutic agent for Alzheimer’s disease (AD). A novel series of 5,6,7,8-tetrahydro[1,2,4]triazolo[4,3-a]pyridine derivatives was discovered and characterized as GSMs. Optimization of substituents at the 8-position of the core scaffold using ligand-lipophilicity efficiency (LLE) as a drug-likeness guideline led to identification of various types of high-LLE GSMs. Phenoxy compound (R)-17 exhibited especially high LLE as well as potent in vivo Aβ42-lowering effect by single administration. Furthermore, multiple oral administration of (R)-17 significantly reduced soluble and insoluble brain Aβ42, and ameliorated cognitive deficit in novel object recognition test (NORT) using Tg2576 mice as an AD model.
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Journal: Bioorganic & Medicinal Chemistry - Volume 24, Issue 14, 15 July 2016, Pages 3192–3206