1131735-01-7Relevant academic research and scientific papers
The discovery of reverse tricyclic pyridone JAK2 inhibitors. Part 2: Lead optimization
Siu, Tony,Kumarasinghe, Sathyajith E.,Altman, Michael D.,Katcher, Matthew,Northrup, Alan,White, Catherine,Rosenstein, Craig,Mathur, Anjili,Xu, Lin,Chan, Grace,Bachman, Eric,Bouthillette, Melaney,Dinsmore, Christopher J.,Marshall, C. Gary,Young, Jonathan R.
, p. 1466 - 1471 (2014/03/21)
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.
INHIBITORS OF JANUS KINASES
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Page/Page column 91, (2009/04/25)
The instant invention provides for compounds that inhibit the four known mammalian JAK kinases (JAK1, JAK2, JAK3 and TYK2) and PDK1. The invention also provides for compositions comprising such inhibitory compounds and methods of inhibiting the activity of JAK1, JAK2, JAK3 TYK2 and PDK1 by administering the compound to a patient in need of treatment for myeloproliferative disorders or cancer.
