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

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

doi:10.1016/j.bmc.2018.02.036

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

Bioorg Med Chem. 2018 May 1;26(8):1896-1908. doi: 10.1016/j.bmc.2018.02.036. Epub 2018 Feb 22.

Authors

Shuangjie Shu¹, Antao Dai², Jiang Wang¹, Bin Wang¹, Yang Feng², Jia Li¹, Xiaoqing Cai², Dehua Yang³, Dakota Ma², Ming-Wei Wang⁴, Hong Liu⁵

Affiliations

¹ State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zu Chong Zhi Road, Shanghai 201203, China; The CAS Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences (CAS), 555 Zu Chong Zhi Road, Shanghai 201203, China; University of Chinese Academy of Sciences, 19A Yuquan Road, Beijing 100049, China.
² The National Center for Drug Screening, 189 Guo Shou Jing Road, Shanghai 201203, China.
³ The CAS Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences (CAS), 555 Zu Chong Zhi Road, Shanghai 201203, China; The National Center for Drug Screening, 189 Guo Shou Jing Road, Shanghai 201203, China.
⁴ The CAS Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences (CAS), 555 Zu Chong Zhi Road, Shanghai 201203, China; The National Center for Drug Screening, 189 Guo Shou Jing Road, Shanghai 201203, China; School of Pharmacy, Fudan University, 826 Zhangheng Road, Shanghai 201203, China. Electronic address: mwwang@simm.ac.cn.
⁵ State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zu Chong Zhi Road, Shanghai 201203, China; The CAS Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences (CAS), 555 Zu Chong Zhi Road, Shanghai 201203, China; University of Chinese Academy of Sciences, 19A Yuquan Road, Beijing 100049, China. Electronic address: hliu@simm.ac.cn.

PMID: 29523469
DOI: 10.1016/j.bmc.2018.02.036

Abstract

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 μM, 0.06 μM, 0.07 μM and 0.08 μM, respectively) and cyclic-adenosine monophosphate (cAMP) activities (IC₅₀ = 0.22 μM, 0.26 μM, 0.44 μM and 0.46 μM, 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.

Keywords: Binding pocket; Docking study; Glucagon receptor antagonist; Pyrazole derivatives.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Allosteric Regulation
Binding Sites
Cyclic AMP / metabolism
Drug Design*
HEK293 Cells
Humans
Hypoglycemic Agents / chemical synthesis*
Hypoglycemic Agents / metabolism
Molecular Docking Simulation
Protein Binding
Protein Structure, Tertiary
Pyrazoles / chemistry*
Pyrazoles / metabolism
Receptors, Glucagon / antagonists & inhibitors*
Receptors, Glucagon / genetics
Receptors, Glucagon / metabolism
Structure-Activity Relationship

Substances

Hypoglycemic Agents
Pyrazoles
Receptors, Glucagon
Cyclic AMP