新型喹啉类化合物的合成及其DPP-4抑制作用

Synthesis of Novel Quinoline Derivatives and Evaluation of Their DPP-4 Inhibition Activities

二肽基肽酶-4(DPP-4)被普遍认为是最具前景的2型糖尿病治疗靶点之一。本文以联苯化合物A7为先导化合物设计并合成了10个未见文献报道的2-(2,4-二氯苯基)-3-氨甲基-4-取代-6-取代喹啉衍生物(B1～B10),并测定其对DPP-4的抑制率和IC_(50)值。目标化合物通过引入的氮原子和芳香环可增强与酶Arg 125和Tyr 547残基的作用。其中,B2～B5(IC_(50)=0.080～0.331μmol/L)和B7～B10(IC_(50)=0.104～0.509μmol/L)显示出较好的体外抑制活性,与阳性对照药西格列汀(IC_(50)=0.035μmol/L)相当。

Dipeptidyl peptidase-4 (DPP-4) inhibitors have been generally considered as one of the most promising targets for treatment of type 2 diabetes. Ten novel 3-aminomethyl-2-(2,4-dichlorophenyl)-4,6-disubstituted quinoline derivatives (B1 - B10) were designed and synthesized with diphenyl compound A7 as the leading compound. The inhibition and IC50 values on DPP-4 of all the compounds were determined. The compounds showed potential activity probably by the interaction of N atom with Arg 125 residue and benzene ring in quinoline with Tyr 547 residue. Compounds B2 - B5 (IC50=0.080 - 0.331 μmol/L) and B7 - B10 (IC50=0.104 - 0.509 μmol/L) displayed the in vitro inhibitory activity similar to the positive control sitagliptin (IC50=0.035 μmol/L).