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Discovery of potent and selective pyrazolopyrimidine janus kinase 2 inhibitors.

Hanan E.J., van Abbema A., Barrett K., Blair W.S., Blaney J., Chang C., Eigenbrot C., Flynn S., Gibbons P., Hurley C.A., Kenny J.R., Kulagowski J., Lee L., Magnuson S.R., Morris C., Murray J., Pastor R.M., Rawson T., Siu M., Ultsch M., Zhou A., Sampath D., Lyssikatos J.P.

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.

J. Med. Chem. 55:10090-10107(2012) [PubMed] [Europe PMC]