OSI Pharmaceuticals LLC, 1 Bioscience Park Drive, Farmingdale, NY 11735, USA.
Bioorg Med Chem Lett. 2013 Aug 15;23(16):4511-6. doi: 10.1016/j.bmcl.2013.06.054. Epub 2013 Jun 27.
The kinase selectivity and pharmacokinetic optimization of a series of 7-aminofuro[2,3-c]pyridine inhibitors of TAK1 is described. The intersection of insights from molecular modeling, computational prediction of metabolic sites, and in vitro metabolite identification studies resulted in a simple and unique solution to both of these problems. These efforts culminated in the discovery of compound 13a, a potent, relatively selective inhibitor of TAK1 with good pharmacokinetic properties in mice, which was active in an in vivo model of ovarian cancer.
本文描述了一系列新型 7-氨基呋喃并[2,3-c]吡啶类 TAK1 激酶抑制剂的激酶选择性和药代动力学优化。分子模拟、代谢部位的计算预测和体外代谢产物鉴定研究的综合结果为这两个问题提供了一个简单而独特的解决方案。这些努力的最终成果是发现了化合物 13a，它是一种强效、相对选择性的 TAK1 抑制剂，在小鼠中的药代动力学性质良好，在卵巢癌的体内模型中具有活性。
