Chin. J. Org. Chem. ›› 2018, Vol. 38 ›› Issue (11): 3086-3093.DOI: 10.6023/cjoc201805020 Previous Articles     Next Articles


N-苯基吡唑脲类FAK II型抑制剂的结构优化与构效关系研究

龚超超, 谈寒一, 张倩   

  1. 复旦大学药学院药物化学教研室 上海 201203
  • 收稿日期:2018-05-08 修回日期:2018-06-07 发布日期:2018-06-29
  • 通讯作者: 张倩
  • 基金资助:


Structure Optimization and Structure-Activity Relationship Study of a Kind of Type II FAK Inhibitors with N-Phenylpyrazole Ureas

Gong Chaochao, Tan Hanyi, Zhang Qian   

  1. Department of Medicinal Chemistry, School of Pharmacy, Fudan University, Shanghai 201203
  • Received:2018-05-08 Revised:2018-06-07 Published:2018-06-29
  • Supported by:

    Project supported by the Shanghai Science and Technology Commission Support Project for Biological Medicine (No. 14431900600) and the School of Pharmacy of Fudan University Fusion Fund (No. RO-MY201708).

The structure modification and optimization focused on the N-phenylpyrazole motif of the lead compound 2 were conducted on basis of the structural features of focal adhesion kinase (FAK) allosteric hydrophobic pockets. Nine aimed compounds were designed and synthesized, among which four compounds maintained the inhibitory activity against FAK at the same level as 2. Especially, N-(4-(5-(3-(4-(6-amino-9H-purin-9-yl) phenyl) ureido)-3-(tert-butyl)-1H-pyrazol-1-yl) phenyl) ace-tamide (9e) demonstrated 2-fold higher inhibition potency than that of the lead compound with the IC50 value of 41 nmol/L. It is suggested that the bioactivity could be further improved by introducing more proper groups at the 4-position of phenyl to increase the interactions between the substituents and the residues around them.

Key words: focal adhesion kinase, allosteric hydrophobic pocket, type II inhibitor, N-phenylpyrazole, structure optimization