Details

Autor(en) / Beteiligte

• Hanan, Emily J
• van Abbema, Anne
• Barrett, Kathy
• Blair, Wade S
• Blaney, Jeff
• Chang, Christine
• Eigenbrot, Charles
• Flynn, Sean
• Gibbons, Paul
• Hurley, Christopher A
• Kenny, Jane R
• Kulagowski, Janusz
• Lee, Leslie
• Magnuson, Steven R
• Morris, Claire
• Murray, Jeremy
• Pastor, Richard M
• Rawson, Tom
• Siu, Michael
• Ultsch, Mark
• Zhou, Aihe
• Sampath, Deepak
• Lyssikatos, Joseph P

Titel

Discovery of Potent and Selective Pyrazolopyrimidine Janus Kinase 2 Inhibitors

Ist Teil von

• Journal of medicinal chemistry, 2012-11, Vol.55 (22), p.10090-10107

Ort / Verlag

United States: American Chemical Society

Erscheinungsjahr

2012

Quelle

MEDLINE

Beschreibungen/Notizen

• The discovery of somatic Jak2 mutations in patients with chronic myeloproliferative neoplasms has led to significant interest in discovering selective Jak2 inhibitors for use in treating these disorders. A high-throughput screening effort identified the pyrazolo[1,5-a]pyrimidine scaffold as a potent inhibitor of Jak2. Optimization of lead compounds 7a–b and 8 in this chemical series for activity against Jak2, selectivity against other Jak family kinases, and good in vivo pharmacokinetic properties led to the discovery of 7j. In a SET2 xenograft model that is dependent on Jak2 for growth, 7j demonstrated a time-dependent knock-down of pSTAT5, a downstream target of Jak2.