A novel series of 4-methyl substituted pyrazole derivatives as potent glucagon receptor antagonists: Design, synthesis and evaluation of biological activities

作者：Shu, Shuangjie; Dai, Antao; Wang, Jiang; Wang, Bin; Feng, Yang; Li, Jia; Cai, Xiaoqing; Yang, Dehua; Ma, Dakota; Wang, Ming-Wei^*; Liu, Hong^*

来源：Bioorganic & Medicinal Chemistry, 2018, 26(8): 1896-1908.

DOI：10.1016/j.bmc.2018.02.036

• Pyrazole derivatives
• Glucagon receptor antagonist
• Docking study
• Binding pocket

A novel series of 4-methyl substituted pyrazole derivatives were designed, synthesized and biologically evaluated as potent glucagon receptor (GCGR) antagonists. In this study, compounds 9q, 9r, 19d and 19e showed high GCGR binding (IC50 = 0.09 mu M, 0.06 mu M, 0.07 mu M and 0.08 mu M, respectively) and cyclic-adenosine monophosphate (cAMP) activities (IC50 = 0.22 mu M, 0.26 mu M, 0.44 mu M and 0.46 mu M, respectively) in cell-based assays. Most importantly, the docking experiment demonstrated that compound 9r formed extensive hydrophobic interactions with the receptor binding pocket, making it justifiable to further investigate the potential of becoming a GCGR antagonist.

• 出版日期2018-5-1
• 单位中国科学院; 国家新药筛选中心; 中国科学院上海药物研究所; 新药研究国家重点实验室; 中国科学院大学; 复旦大学