1.
J Med Chem
; 55(22): 10090-107, 2012 Nov 26.
Article
in English
| MEDLINE
| ID: mdl-23061660
ABSTRACT
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.