Gellibert F, Fouchet M-H, Nguyen V-L, Wang R, Krysa G, de Gouville A-C, Huet S, Dodic N
GlaxoSmithKline, Les Ulis, France.
Bioorg Med Chem Lett. 2009 Apr 15;19(8):2277-81. doi: 10.1016/j.bmcl.2009.02.087. Epub 2009 Feb 26.
Starting from quinazoline 3a, we designed potent and selective ALK5 inhibitors over p38MAP kinase from a rational drug design approach based on co-crystal structures in the human ALK5 kinase domain. The quinazoline 3d exhibited also in vivo activity in an acute rat model of DMN-induced liver fibrosis when administered orally at 5mg/kg (bid).
从喹唑啉3a开始，我们基于人ALK5激酶结构域的共晶体结构，通过合理的药物设计方法，设计出了对p38丝裂原活化蛋白激酶具有强效和选择性的ALK5抑制剂。喹唑啉3d在以5mg/kg（每日两次）口服给药时，在二甲基亚硝胺诱导的大鼠急性肝纤维化模型中也表现出体内活性。
