期刊
JOURNAL OF MEDICINAL CHEMISTRY
卷 55, 期 22, 页码 10090-10107出版社
AMER CHEMICAL SOC
DOI: 10.1021/jm3012239
关键词
-
资金
- Office of Science, Office of Basic Energy Sciences, of the U.S. Department of Energy [DE-AC02-05CH11231]
The discovery of somatic Jak2 mutations in patients with chronic myeloproliferative neoplasms has led to significant interest in disc-ova-ring 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 inhibit-or 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.
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