Pharmaceutical Research Division, Takeda Pharmaceutical Company Limited, 17-85, Jusohomachi 2-chome, Yodogawa-ku, Osaka 532-8686, Japan.
Bioorg Med Chem. 2011 Aug 1;19(15):4482-98. doi: 10.1016/j.bmc.2011.06.032. Epub 2011 Jul 7.
Dipeptidyl peptidase IV (DPP-4) inhibition is a validated therapeutic option for type 2 diabetes, exhibiting multiple antidiabetic effects with little or no risk of hypoglycemia. In our studies involving non-covalent DPP-4 inhibitors, a novel series of quinoline-based inhibitors were designed based on the co-crystal structure of isoquinolone 2 in complex with DPP-4 to target the side chain of Lys554. Synthesis and evaluation of designed compounds revealed 1-[3-(aminomethyl)-4-(4-methylphenyl)-2-(2-methylpropyl)quinolin-6-yl]piperazine-2,5-dione (1) as a potent, selective, and orally active DPP-4 inhibitor (IC₅₀=1.3 nM) with long-lasting ex vivo activity in dogs and excellent antihyperglycemic effects in rats. A docking study of compound 1 revealed a hydrogen-bonding interaction with the side chain of Lys554, suggesting this residue as a potential target site useful for enhancing DPP-4 inhibition.
二肽基肽酶 4（DPP-4）抑制是治疗 2 型糖尿病的一种有效方法，具有多种抗糖尿病作用，且低血糖风险低或无风险。在我们涉及非共价 DPP-4 抑制剂的研究中，根据异喹啉 2 与 DPP-4 形成复合物的共晶结构，设计了一系列新型基于喹啉的抑制剂，以靶向 Lys554 的侧链。设计化合物的合成和评估揭示了 1-[3-(氨甲基)-4-(4-甲基苯基)-2-(2-甲基丙基)喹啉-6-基]哌嗪-2,5-二酮（1）是一种有效的、选择性的、口服活性的 DPP-4 抑制剂（IC₅₀=1.3 nM），在狗体内具有持久的体外活性，在大鼠体内具有良好的降血糖作用。化合物 1 的对接研究显示与 Lys554 的侧链存在氢键相互作用，表明该残基是增强 DPP-4 抑制的潜在靶位。
