氰基吡咯烷类DPP-4抑制剂的设计、合成及活性研究

Design,synthesis and characterization of cyanopyrrolidine-bearing compounds as DPP-4 inhibitors

目的设计合成底物类似的氰基吡咯烷类二肽基肽酶（DPP-4）抑制剂,对其进行体外活性测试。方法以氰基吡咯烷为基本骨架,引入不同的取代基,设计了11个DPP-4抑制剂。以L-脯氨酰胺为原料制备溴乙酰氰基吡咯烷,再与不同取代的苯基哌嗪哒嗪酮经亲核取代反应得目标化合物。结果所得目标化合物经~1H-NMR、MS确认结构,并以西他列汀为对照药,对其进行体外活性筛选。所有目标化合物均有一定的抑制活性。结论活性测试显示11个目标位均有一定的DPP-4抑制活性,其中化合物1j和1k的抑制活性更强,在10~5nmol/L水平的抑制率分别是1j（26.14%）、1k（34.15%）。

Objective To synthesize novel cyanopyrrolidine-bearing compounds as dipeptidyl peptidase 4（DPP4） inhibitors and characterize their biological activities in vitro.Methods Eleven analogues of carbonitrilpyrrolidine were designed and synthesized by substitution reaction of（S）-2-（2-cyanopyrrolidin-l-yl）acetyl bromide with substituted phenyl piperazine pyridazinones.Results The structures of the compounds were characterized by ~1H-NMR and MS spectra.Biological evaluation indicated that most of the compounds exhibited moderate inhibitory activities against DPP4.Conclusion The preliminary bioassay indicates that all the synthesized compounds have moderate DPP-4 inhibition activity,especially the compounds 1j and 1k with inhibition rates reaching 26.14%and 34.15%at the concentration of 1×10~5 nmol/L,respectively.