A novel series of 4-methyl substituted pyrazole derivatives as potent glucagon receptor antagonists: Design, synthesis and evaluation of biological activities. Issue 8 (1st May 2018)

• Record Type: Journal Article
• Authors: Shu, Shuangjie; Dai, Antao; Wang, Jiang; Wang, Bin; Feng, Yang; Li, Jia; Cai, Xiaoqing; Yang, Dehua; Ma, Dakota; Wang, Ming-Wei; Liu, Hong
• Is Part Of: Bioorganic & medicinal chemistry. Volume 26:Issue 8(2018)
• Page Start: 1896
• Page End: 1908
• Publication Date: 2018-05-01
• Subjects: GCGR glucagon receptor -- cAMP cyclic-adenosine monophosphate -- T2DM type 2 diabetes mellitus -- SGLT-2 sodium-glucose cotransporter-2 -- HGP hepatic glucose production -- GPCRs G-protein coupled receptors -- SAR structure-activity relationship -- Ser Serine -- Arg Arginine -- Asn Asparagine -- Lys Lysine -- Leu Leucine -- Thr Threonine -- Phe Phenylalanine -- Ala Alanine; Pyrazole derivatives -- Glucagon receptor antagonist -- Docking study -- Binding pocket; Bioorganic chemistry -- Periodicals; Pharmaceutical chemistry -- Periodicals; Biochemistry -- Periodicals; Chemistry, Clinical -- Periodicals; Chemistry, Organic -- Periodicals; Chimie bio-organique -- Périodiques; Chimie pharmaceutique -- Périodiques; 615.19
• DOI: 10.1016/j.bmc.2018.02.036
• Languages: English
• ISSNs: 0968-0896

Abstract

Graphical abstract: 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.