کد مقاله | کد نشریه | سال انتشار | مقاله انگلیسی | نسخه تمام متن |
---|---|---|---|---|
10586926 | 981411 | 2014 | 6 صفحه PDF | دانلود رایگان |
عنوان انگلیسی مقاله ISI
The discovery of reverse tricyclic pyridone JAK2 inhibitors. Part 2: Lead optimization
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کلمات کلیدی
موضوعات مرتبط
مهندسی و علوم پایه
شیمی
شیمی آلی
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چکیده انگلیسی
This communication discusses the discovery of novel reverse tricyclic pyridones as inhibitors of Janus kinase 2 (JAK2). By using a kinase cross screening approach coupled with molecular modeling, a unique inhibitor-water interaction was discovered to impart excellent broad kinase selectivity. Improvements in intrinsic potency were achieved by utilizing a rapid library approach, while targeted structural changes to lower lipophilicity led to improved rat pharmacokinetics. This multi-pronged approach led to the identification of 31, which demonstrated encouraging rat pharmacokinetics, in vivo potency, and excellent off-target kinase selectivity.
ناشر
Database: Elsevier - ScienceDirect (ساینس دایرکت)
Journal: Bioorganic & Medicinal Chemistry Letters - Volume 24, Issue 6, 15 March 2014, Pages 1466-1471
Journal: Bioorganic & Medicinal Chemistry Letters - Volume 24, Issue 6, 15 March 2014, Pages 1466-1471
نویسندگان
Tony Siu, Sathyajith E. Kumarasinghe, Michael D. Altman, Matthew Katcher, Alan Northrup, Catherine White, Craig Rosenstein, Anjili Mathur, Lin Xu, Grace Chan, Eric Bachman, Melaney Bouthillette, Christopher J. Dinsmore, C. Gary Marshall,