Xin Minhang, Zhang Liandi, Tang Feng, Tu Chongxing, Wen Jun, Zhao Xinge, Liu Zhaoyu, Cheng Lingfei, Shen Han
Department of Medicinal Chemistry, School of Pharmacy, Health Science Center, Xi'an Jiaotong University, No. 76, Yanta West Road, Xi'an 710061, PR China; Jiangsu Simcere Pharmaceutical Co. Ltd, Jiangsu Key Laboratory of Molecular Targeted Antitumor Drug Research, No 699-18, Xuan Wu District, Nanjing 210042, PR China.
Jiangsu Simcere Pharmaceutical Co. Ltd, Jiangsu Key Laboratory of Molecular Targeted Antitumor Drug Research, No 699-18, Xuan Wu District, Nanjing 210042, PR China.
Bioorg Med Chem. 2014 Feb 15;22(4):1429-40. doi: 10.1016/j.bmc.2013.12.055. Epub 2014 Jan 3.
A novel series of Hh signaling pathway inhibitors were designed by replacing the pyrimidine skeleton of our earlier reported lead compound 1 with pyrrolo[2,1-f][1,2,4]triazine scaffold. Starting from this new scaffold, SAR exploration was investigated based on structural modification on A-ring, C-ring and D-ring. And several much potent compounds were studies in vivo to profile their pharmacokinetic properties. Finally, optimization leads to the identification of compound 19a, a potent Hh signaling pathway inhibitor with superior potency in vitro and satisfactory pharmacokinetic properties in vivo.
通过用吡咯并[2,1-f][1,2,4]三嗪骨架取代我们早期报道的先导化合物1的嘧啶骨架，设计了一系列新型的Hh信号通路抑制剂。从这个新骨架开始，基于对A环、C环和D环的结构修饰进行了构效关系研究。并对几种活性更强的化合物进行了体内研究，以分析它们的药代动力学性质。最后，经过优化得到了化合物19a，它是一种有效的Hh信号通路抑制剂，具有优异的体外活性和令人满意的体内药代动力学性质。
