Discovery and optimization of 7-aminofuro[2,3-c]pyridine inhibitors of TAK1

Abstract The discovery and potency optimization of a series of 7-aminofuro[2,3- c ]pyridine inhibitors of TAK1 is described. Micromolar hits taken from high-throughput screening were optimized for biochemical and cellular mechanistic potency to ∼10 nM, as exemplified by compound 12az . Application of structure-based drug design aided by co-crystal structures of TAK1 with inhibitors significantly shortened the number of iterations required for the optimization.