Structural optimization of pyrazolo[1,5-a]pyrimidine derivatives as potent and highly selective DPP-4 inhibitors

摘要: Abstract Our previous discovery of pyrazolo [1,5-a]pyrimidin-7(4H)-one scaffold-based DPP-4 inhibitors yielded two potent compounds b2 (IC50 = 79 nM) and d1 (IC50 = 49 nM) but characterized by cytotoxicity. Herein, with scaffold hopping fragment-based drug design strategies, highly selective [1,5-a]pyrimidine were found featured reduced or diminished Specifically, c24 (IC50 = 2 nM) exhibits a 25 to 40-fold increase inhibitory activity respect those d1, respectively, 2-fold from Alogliptin (IC50 = 4 nM), remarkable selectivity over DPP-8 DPP-9 (>2000 fold). Further docking studies confirmed that the core interacts S1 pocket whereas its substituted aromatic ring sub-S1 pocket. The interactive mode in this case resembles Trelagliptin. in vivo IPGTT assays diabetic mice demonstrated effectively reduces glucose excursion 48% at dose 10 mg/kg, suggesting is worthy further development as anti-diabetes agent.