OSI Pharmaceuticals LLC, 1 Bioscience Park Drive, Farmingdale, NY 11735, USA.
Bioorg Med Chem Lett. 2013 Aug 15;23(16):4517-22. doi: 10.1016/j.bmcl.2013.06.053. Epub 2013 Jun 25.
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 ~10nM, 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.
本文描述了一系列 7-氨基呋喃并[2,3-c]吡啶 TAK1 抑制剂的发现和效力优化。高内涵筛选得到的微摩尔起始物经过优化，以达到生化和细胞机制效力的纳摩尔水平，化合物 12az 就是一个很好的例子。通过与抑制剂的共晶结构进行基于结构的药物设计应用，大大缩短了优化所需的迭代次数。
