Diaminopyrimidine-based Syk inhibitors

Cross-reactivity with JAK kinases is a recurring theme with pyrimidine-carboxamides [81,82], but compound 20 exemplifies a Syk-selective series [81]. Pyrimidine amide 20 has an IC50 of 6nM against Syk, and broad screening (at 300 nM concentration) demonstrated significant selectivity for Syk over 270 kinases. In Ramos cells, 20 inhibited BCR-induced phosphorylation of BLNK, a direct substrate of Syk, with an EC50 of 500-750 nM and Ca2+ flux with an EC50 = 117 nM. Compound 20 potently 

The diaminopyrimidine has been incorporated into a pyrrolopyrimi-dine scaffold exemplified by 21 [83]. This framework appears in several patent applications [84-87] claiming Syk activity of 1 fiM. 

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