Synthesis and SAR of new pyrrolo[2,1- f][1,2,4]triazines as potent p38α MAP kinase inhibitors

Synthesis of a novel series of substituted pyrrolo[2,1- f][1,2,4]triazines have resulted in the identification of subnanomolar inhibitors of the p38α MAP kinase. Subsequent X-ray co-crystallographic studies with compound 30 have revealed the binding mode of this class of inhibitors within the p38α active site. A novel series of compounds based on the pyrrolo[2,1- f][1,2,4]triazine ring system have been identified as potent p38α MAP kinase inhibitors. The synthesis, structure–activity relationships (SAR), and in vivo activity of selected analogs from this class of inhibitors are reported. Additional studies based on X-ray co-crystallography have revealed that one of the potent inhibitors from this series binds to the DFG-out conformation of the p38α enzyme.