7-Aminopyrazolo1,5-apyrimidines as potent multitargeted receptor tyrosine kinase inhibitors

摘要

7-Aminopyrazolo1,5-apyrimidine urea receptor tyrosine kinase inhibitors have been discovered. Investigation of structure-activity relationships of the pyrazolo1,5-apyrimidine nucleus led to a series of 6-(4-N,N'-diphenyl)ureas that potently inhibited a panel of vascular endothelial growth factor receptor (VEGFR) and platelet-derived growth factor receptor (PDGFR) kinases. Several of these compounds, such as 34a, are potent inhibitors of kinase insert domain-containing receptor tyrosine kinase (KDR) both enzymatically (< 10 nM) and cellularly (< 10 nM). In addition, compound 34a possesses a favorable pharmacokinetic profile and demonstrates efficacy in the estradiol-induced murine uterine edema (UE) model (ED50 = 1.4 mg/kg).