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 Med Chem. 2019 Feb 15;27(4):644-654. doi: 10.1016/j.bmc.2019.01.001. Epub 2019 Jan 4.
Dipeptidyl Peptidase-IV (DPP-4) is a validated therapeutic target for type 2 diabetes. Aiming to interact with both residues Try629 and Lys554 in S' site, a series of novel uracil derivatives 1a-l and 2a-i incorporating benzoic acid moieties at the N position were designed and evaluated for their DPP-4 inhibitory activity. Structure-activity relationships (SAR) study led to the identification of the optimal compound 2b as a potent and selective DPP-4 inhibitor (IC = 1.7 nM). Docking study revealed the additional salt bridge formed between the carboxylic acid and primary amine of Lys554 has a key role in the enhancement of the activity. Furthermore, compound 2b exhibited no cytotoxicity in human hepatocyte LO2 cells up to 50 μM. Subsequent in vivo evaluations revealed that the ester of 2b robustly improves the glucose tolerance in normal mice. The overall results have shown that compound 2b has the potential to a safe and efficacious treatment for T2DM.
二肽基肽酶-4（DPP-4）是 2 型糖尿病的一个已验证的治疗靶点。本研究旨在与 S'位的 Try629 和 Lys554 两个残基相互作用，设计并评价了一系列在 N 位引入苯甲酸部分的新型尿嘧啶衍生物 1a-l 和 2a-i，以评估它们对 DPP-4 的抑制活性。构效关系（SAR）研究确定了最佳化合物 2b 是一种有效的、选择性的 DPP-4 抑制剂（IC=1.7nM）。对接研究表明，Lys554 的仲胺与羧酸形成的额外盐桥在提高活性方面起着关键作用。此外，化合物 2b 在 50µM 以内对人肝细胞 LO2 细胞无细胞毒性。随后的体内评价表明，2b 的酯在正常小鼠中可显著改善葡萄糖耐量。总的来说，这些结果表明，化合物 2b 有可能成为治疗 2 型糖尿病的一种安全有效的药物。
