Surrogating and redirection of Pyrazolo[1,5-a]pyrimidin-7(4H)-one core, a novel class of potent and selective DPP-4 Inhibitors

Publication date: Available online 10 January 2018
Source:Bioorganic & Medicinal Chemistry
Author(s): Xinxian Deng, Jian Shen, Hui Zhu, Jia Xiao, Ran Sun, Fangzhou Xie, Celine Lam, Juntao Wang, Yixue Qiao, Mojdeh S. Tavallaie, Yang Hu, Yi Du, Jianqi Li, Lei Fu, Faqin Jiang
The initial focus on characterizing novel pyrazolo[1,5-a]pyrimidin-7(4H)-one derivatives as DPP-4 inhibitors, led to a potent and selective inhibitor compound b2. This ligand exhibits potent in vitro DPP-4 inhibitory activity (IC50: 80 nM), whilst maintaining other key cellular parameters such as high selectivity, low cytotoxicity and good cell viability. Subsequent optimization of b2 based on docking analysis and structure-based drug design knowledge resulted in d1. Compound d1 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 compound b2 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(4H)-one DPP-4 inhibitors.

Graphical abstract

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