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
موضوعات مرتبط
مهندسی و علوم پایه شیمی شیمی آلی
پیش نمایش صفحه اول مقاله
The discovery of reverse tricyclic pyridone JAK2 inhibitors. Part 2: Lead optimization
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
نویسندگان
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