2. Academic Validation
  3. Design, synthesis and biological evaluation of thieno[3,2-c]pyrazol-urea derivatives as potent glycogen synthase kinase 3β inhibitors based on the DFG-out conformation

Design, synthesis and biological evaluation of thieno[3,2-c]pyrazol-urea derivatives as potent glycogen synthase kinase 3β inhibitors based on the DFG-out conformation

  • Bioorg Med Chem Lett. 2024 Nov 1:112:129932. doi: 10.1016/j.bmcl.2024.129932.
Ning Yan 1,  Hong-Yan Liu 2,  Ting-Ting Kong 3,  Zi-Hao Kong 1,  Ling-Yun Li 1,  Xin Ma 1,  Yan-Li Zeng 1,  Mei-Jun Wang 1,  Long-Qian Tang 1,  Cheng-Mei Zhang 4,  Zhao-Peng Liu 5,  Chao Liu 6
Affiliations

Affiliations

  • 1 Department of Medicinal Chemistry, Key Laboratory of Chemical Biology (Ministry of Education), School of Pharmaceutical Sciences, Cheeloo College of Medicine, Shandong University, Jinan 250012, PR China.
  • 2 The People's Hospital of Zhaoyuan City, No. 168 Yingbin Road, Zhaoyuan 265400, PR China.
  • 3 Department of Pharmacy, Qilu Hospital of Shandong University, Shandong University, Jinan 250012, PR China.
  • 4 Department of Medicinal Chemistry, Key Laboratory of Chemical Biology (Ministry of Education), School of Pharmaceutical Sciences, Cheeloo College of Medicine, Shandong University, Jinan 250012, PR China. Electronic address: zhangcm@sdu.edu.cn.
  • 5 Department of Medicinal Chemistry, Key Laboratory of Chemical Biology (Ministry of Education), School of Pharmaceutical Sciences, Cheeloo College of Medicine, Shandong University, Jinan 250012, PR China. Electronic address: liuzhaop@sdu.edu.cn.
  • 6 Department of Medicinal Chemistry, Key Laboratory of Chemical Biology (Ministry of Education), School of Pharmaceutical Sciences, Cheeloo College of Medicine, Shandong University, Jinan 250012, PR China. Electronic address: chaoliu@sdu.edu.cn.
PMID: 39182737 DOI: 10.1016/j.bmcl.2024.129932
Abstract

Glycogen synthase kinase 3β (GSK-3β) is a potential therapeutic target for the treatment of a variety of human diseases. Here, we report the design and synthesis of a series of thieno[3,2-c]pyrazol-urea derivatives and evaluation of their GSK-3β inhibitory activity. Among these analogues, the compound without substitution on terminal phenyl ring (3a) was found to be the most potent GSK-3β Inhibitor with an IC50 of 74.4 nM, while substitution on the terminal phenyl (3b-3p) led to decreased potency, independent of the position, size, or electronic properties of the substituents. Kinase selectivity assay revealed that 3a showed good selectivity over a panel of kinases, but was less selective over CDK1, CDK2 and CDK5. Additionally, the pharmacological properties of the synthesized compounds were investigated computationally by the SwissADME and the results showed that most of the compounds have good ADME profiles.

Keywords

DFG-out conformation; DOLPHIN protocol; GSK-3β; GSK-3β inhibitors; Type II GSK-3β inhibitors.

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