Citation: 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]. Chinese Journal of Organic Chemistry, ;2018, 38(11): 3086-3093. doi: 10.6023/cjoc201805020 shu

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

Department of Medicinal Chemistry, School of Pharmacy, Fudan University, Shanghai 201203

Corresponding author: Zhang Qian, zhangqian511@shmu.edu.cn
Received Date: 8 May 2018
Revised Date: 7 June 2018
Available Online: 29 November 2018
Fund Project: the School of Pharmacy of Fudan University Fusion Fund RO-MY201708Project 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 Shanghai Science and Technology Commission Support Project for Biological Medicine 14431900600

Figures(6)

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.
- focal adhesion kinase,
- allosteric hydrophobic pocket,
- type Ⅱ inhibitor,
- N-phenylpyrazole,
- structure optimization
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