کد مقاله | کد نشریه | سال انتشار | مقاله انگلیسی | نسخه تمام متن |
---|---|---|---|---|
10592501 | 981794 | 2012 | 5 صفحه PDF | دانلود رایگان |
عنوان انگلیسی مقاله ISI
Lead optimization of 4,4-biaryl piperidine amides as γ-secretase inhibitors
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موضوعات مرتبط
مهندسی و علوم پایه
شیمی
شیمی آلی
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چکیده انگلیسی
Alzheimer's disease is a major unmet medical need with pathology characterized by extracellular proteinaceous plaques comprised primarily of β-amyloid. γ-Secretase is a critical enzyme in the cellular pathway responsible for the formation of a range of β-amyloid peptides; one of which, Aβ42, is believed to be responsible for the neuropathological features of the disease. Herein, we report 4,4 disubstituted piperidine γ-secretase inhibitors that were optimized for in vitro cellular potency and pharmacokinetic properties in vivo. Key agents were further characterized for their ability to lower cerebral Aβ42 production in an APP-YAC mouse model. This structural series generally suffered from sub-optimal pharmacokinetics but hypothesis driven lead optimization enabled the discovery of γ-secretase inhibitors capable of lowering cerebral Aβ42 production in mice.
ناشر
Database: Elsevier - ScienceDirect (ساینس دایرکت)
Journal: Bioorganic & Medicinal Chemistry Letters - Volume 22, Issue 9, 1 May 2012, Pages 3203-3207
Journal: Bioorganic & Medicinal Chemistry Letters - Volume 22, Issue 9, 1 May 2012, Pages 3203-3207
نویسندگان
Joshua Close, Richard Jr., John Hendrix, Chaomin Li, Ben Munoz, Laura Surdi, Solomon Kattar, Paul Tempest, Paul Moses, Xiaoliu Geng, Bethany Hughes, Nadya Smotrov, Chris Moxham, Jennifer Chapnick, Ilona Kariv, George Nikov, Julie Elizabeth Burke,