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Discovery of 4-aminomethylphenylacetic acids as γ-secretase modulators via a scaffold design approach

التفاصيل البيبلوغرافية
العنوان: Discovery of 4-aminomethylphenylacetic acids as γ-secretase modulators via a scaffold design approach
المؤلفون: Robert H. Scannevin, Tina Talreja, Lin Xu, Gnanasambandam Kumaravel, David Kocisko, Arthur G. Taveras, Anthone W. Dunah, Hairuo Peng, Kenneth J. Rhodes, Ellen Rohde, H. Moore Arnold, Sowmya Chollate, Pamela A. Snodgrass-Belt, Mi-yong Jung, Andrew Zhang, Zhili Xin, Melanie N. Shackett
المصدر: Bioorganic & Medicinal Chemistry Letters. 21:7277-7280
بيانات النشر: Elsevier BV, 2011.
سنة النشر: 2011
مصطلحات موضوعية: Scaffold, Carboxylic acid, Clinical Biochemistry, Drug Evaluation, Preclinical, Administration, Oral, Pharmaceutical Science, Pharmacology, Biochemistry, Mice, chemistry.chemical_compound, Piperidines, Oral administration, Drug Discovery, Animals, γ secretase, Enzyme Inhibitors, Molecular Biology, Phenylacetates, chemistry.chemical_classification, Amyloid beta-Peptides, Nonsteroidal, Anti-Inflammatory Agents, Non-Steroidal, Organic Chemistry, Brain, Combinatorial chemistry, Peptide Fragments, Rats, chemistry, Drug Design, Molecular Medicine, Amyloid Precursor Protein Secretases
الوصف: Starting from literature examples of nonsteroidal anti-inflammatory drugs (NSAIDs)-type carboxylic acid γ-secretase modulators (GSMs) and using a scaffold design approach, we identified 4-aminomethylphenylacetic acid 4 with a desirable γ-secretase modulation profile. Scaffold optimization led to the discovery of a novel chemical series, represented by 6b, having improved brain penetration. Further SAR studies provided analog 6q that exhibited a good pharmacological profile. Oral administration of 6q significantly reduced brain Aβ42 levels in mice and rats.
تدمد: 0960-894X
URL الوصول: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::fff16ea306e260e39cfe769d34265e32
https://doi.org/10.1016/j.bmcl.2011.10.047
حقوق: CLOSED
رقم الأكسشن: edsair.doi.dedup.....fff16ea306e260e39cfe769d34265e32
قاعدة البيانات: OpenAIRE
الوصف
تدمد:0960894X