1131735-05-1Relevant articles and documents
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.
