Discovery of novel 5,6,7,8-tetrahydro[1,2,4]triazolo[4,3-a]pyridine derivatives as γ-secretase modulators (Part 2)

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• 作者：Takafumi Takai ; ^{takafumi.takai@takeda.com" class="auth_mail" title="E-mail the corresponding author} ; Tatsuki Koike ; Minoru Nakamura ; Yuichi Kajita ; Toshiro Yamashita ; Naohiro Taya ; Tetsuya Tsukamoto ; Tomomichi Watanabe ; Koji Murakami ; Tomoko Igari ; Makoto Kamata
• 关键词：GSM ; γ-secretase modulator ; Aβ ; amyloid beta ; AD ; Alzheimer&rsquo ; s disease ; LLE ; ligand-lipophilicity efficiency ; NORT ; novel object recognition test ; APP ; amyloid precursor protein ; MLM ; mice liver microsomes ; CNS ; central nervous system ; WT ; wild type
• 刊名：Bioorganic & Medicinal Chemistry
• 出版年：2016
• 出版时间：15 July 2016
• 年：2016
• 卷：24
• 期：14
• 页码：3192-3206
• 全文大小：1472 K

文摘

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.