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

doi:10.6023/cjoc201805020

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

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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

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 E-mail:zhangqian511@shmu.edu.cn
基金资助:
上海市科委生物医药支撑（No.14431900600）及复旦大学药学院融合基金（No.RO-MY201708）资助项目.

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

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).

1. Structure Optimization and Structure-Activity Relationship Study of a Kind of Type II FAK Inhibitors with N-Phenylpyrazole Ureas.PDF(866KB)

Abstract

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

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Gong Chaochao, Tan Hanyi, Zhang Qian. Structure Optimization and Structure-Activity Relationship Study of a Kind of Type II FAK Inhibitors with N-Phenylpyrazole Ureas[J]. Chin. J. Org. Chem., 2018, 38(11): 3086-3093.

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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

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

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