Surrogating and redirection of pyrazolo[1, 5-a]pyrimidin-7(4H)-one core, a novel class of potent and selective DPP-4 inhibitors. Issue 4 (15th February 2018)

• Record Type: Journal Article
• Authors: Deng, Xinxian; Shen, Jian; Zhu, Hui; Xiao, Jia; Sun, Ran; Xie, Fangzhou; Lam, Celine; Wang, Juntao; Qiao, Yixue; Tavallaie, Mojdeh S.; Hu, Yang; Du, Yi; Li, Jianqi; Fu, Lei; Jiang, Faqin
• Is Part Of: Bioorganic & medicinal chemistry. Volume 26:Issue 4(2018)
• Page Start: 903
• Page End: 912
• Publication Date: 2018-02-15
• Subjects: DPP-4 inhibitor -- Pyrazolo[1, 5-a]pyrimidin-7(4H)-one derivatives -- Structure-based drug design -- Molecular docking -- Anti-diabetic; 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.2018.01.006
• Languages: English
• ISSNs: 0968-0896

Abstract

Graphical abstract: The initial focus on characterizing novel pyrazolo[1, 5- a ]pyrimidin-7(4 H )-one derivatives as DPP-4 inhibitors, led to a potent and selective inhibitor compoundb2 with remarkable in vitro DPP-4 inhibitory action (IC50 : 80 nM), while maintaining other key cellular parameters such as high selectivity, low cytotoxicity and good cell viability. Subsequent optimization ofb2 based on docking analysis and structure-based drug design knowledge resulted ind1 with nearly 2-fold increase of inhibitory activity (IC50 : 49 nM) and over 1000-fold selectivity against DPP-8 and DPP-9. Further in vivo IPGTT assays showed that compoundb2 effectively reduce glucose excursion by 34% at the dose of 10 mg/kg in diabetic mice. Herein we report the optimization and design of a potent and highly selective series of pyrazolo[1, 5- a ]pyrimidin-7(4 H )-one DPP-4 inhibitors. Abstract: The initial focus on characterizing novel pyrazolo[1, 5- a ]pyrimidin-7(4 H )-one derivatives as DPP-4 inhibitors, led to a potent and selective inhibitor compoundb2 . This ligand exhibits potent in vitro DPP-4 inhibitory activity (IC50 : 80 nM), while maintaining other key cellular parameters such as high selectivity, low cytotoxicity and good cell viability. Subsequent optimization ofb2 based on docking analysis and structure-based drug design knowledge resulted ind1 . Compoundd1 has nearly 2-fold increase of inhibitory activity (IC50 : 49 nM) and over 1000-fold selectivity against DPP-8 and DPP-9. Further in vivo IPGTT assays showed that compoundb2 effectively reduce glucose excursion by 34% at the dose of 10 mg/kg in diabetic mice. Herein we report the optimization and design of a potent and highly selective series of pyrazolo[1, 5- a ]pyrimidin-7(4 H )-one DPP-4 inhibitors.