Pharmaceutical College, Guangxi Medical University, Nanning 530021, China.
Department of Organic Chemistry and State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing 210009, China.
Bioorg Chem. 2020 Jan;94:103366. doi: 10.1016/j.bioorg.2019.103366. Epub 2019 Oct 15.
Our recently successful identification of benzoic acid-based DPP-4 inhibitors spurs the further quest for in-depth structure-activity relationships (SAR) study in S' site DPP-4. Thus novel benzamide fragments were designed to target the S' site to compromise lipophilicity and improve oral activity. Exploring SAR by introduction of a variety of amide and halogen on benzene ring led to identification of several compounds, exerting moderated to excellent DPP-4 activities, in which 4'-chlorine substituted methyl amide 17g showed most potent DPP-4 activity with the IC value of 1.6 nM. Its activity was superior to reference alogliptin. Docking study ideally verified and interpreted the obtained SAR of designed compounds. As a continuation, DPP-8/9 assays revealed the designed compounds exhibited good selectivity over DPP-8 and DPP-9. Subsequent cell-based test indicated compound 17g displayed low toxicity toward the LO2 cell line up to 100 μM. In vivo evaluation showed compound 17g robustly improved the glucose tolerance in normal mice. Importantly, 17g exhibited reasonable pharmacokinetic (PK) profiles for oral delivery. Overall, compound 17g has the potential to a safe and efficacious DPP-4 inhibitor for T2DM treatment.
我们最近成功鉴定了基于苯甲酸的 DPP-4 抑制剂，这激发了我们进一步深入研究 DPP-4 的 S' 位的构效关系（SAR）。因此，我们设计了新的苯甲酰胺片段，以靶向 S' 位，降低亲脂性并提高口服活性。通过在苯环上引入各种酰胺和卤素来探索 SAR，鉴定出了一些化合物，它们对 DPP-4 具有中等至优异的活性，其中 4'-氯取代的甲基酰胺 17g 对 DPP-4 具有最强的活性，IC 值为 1.6 nM。其活性优于参比药物阿格列汀。对接研究理想地验证和解释了设计化合物的获得的 SAR。作为延续，DPP-8/9 测定显示设计的化合物对 DPP-8 和 DPP-9 具有良好的选择性。随后的基于细胞的测试表明，化合物 17g 在 100 µM 时对 LO2 细胞系的毒性较低。体内评估表明，化合物 17g 可显著改善正常小鼠的葡萄糖耐量。重要的是，17g 具有合理的口服药物动力学（PK）特征。总的来说，化合物 17g 有可能成为治疗 T2DM 的安全有效的 DPP-4 抑制剂。
