Deng Xiaoyan, Han Li, Zhou Jinpei, Zhang Huibin, Li Qing
Pharmaceutical College, Guangxi Medical University, Nanning, Guangxi, PR China.
Center of Drug Discovery, Jiangsu Key Laboratory of Drug Discovery for Metabolic Disease, China Pharmaceutical University, Nanjing 210009, PR China.
Bioorg Chem. 2017 Dec;75:357-367. doi: 10.1016/j.bioorg.2017.10.010. Epub 2017 Oct 23.
Dipeptidyl peptidase-IV (DPP-4) is a validated target for T2DM treatment. We previously reported a novel series of triazole-based uracil derivatives bearing aliphatic carboxylic acids with potent DPP-4 inhibitory activities in vitro, but these compounds showed poor hypoglycemic effects in vivo. Herein we further optimized the triazole moiety by amidation of the carboxylic acid to improve in vivo activities. Two series of compounds 3a-f and 4a-g were designed and synthesized. By screening in DPP-4, compound 4c was identified as a potent DPP-4 inhibitor with the IC value of 28.62 nM. Docking study revealed compound 4c has a favorable binding mode and interpreted the SAR of these analogs. DPP-8 and DPP-9 tests indicated compound 4c had excellent selectivity over DPP-8 and DPP-9. Further in vivo evaluations revealed that compound 4c showed more potent hypoglycemic activity than its corresponding carboxylic acid in ICR mice and dose-dependently reduced glucose levels in type 2 diabetic C57BL/6 mice. The overall results have shown that compound 4c could be a promising lead for further development of novel DPP-4 agents treating T2DM.
二肽基肽酶-IV（DPP-4）是2型糖尿病治疗的一个已验证靶点。我们之前报道了一系列新型的带有脂肪族羧酸的基于三唑的尿嘧啶衍生物，它们在体外具有强效的DPP-4抑制活性，但这些化合物在体内显示出较差的降血糖效果。在此，我们通过羧酸的酰胺化进一步优化三唑部分以提高体内活性。设计并合成了两个系列的化合物3a-f和4a-g。通过对DPP-4进行筛选，化合物4c被鉴定为一种强效的DPP-4抑制剂，IC值为28.62 nM。对接研究表明化合物4c具有良好的结合模式，并解释了这些类似物的构效关系。DPP-8和DPP-9测试表明化合物4c对DPP-8和DPP-9具有优异的选择性。进一步的体内评估显示，在ICR小鼠中，化合物4c比其相应的羧酸表现出更强的降血糖活性，并且在2型糖尿病C57BL/6小鼠中能剂量依赖性地降低血糖水平。总体结果表明，化合物4c可能是进一步开发治疗2型糖尿病的新型DPP-4药物的一个有前景的先导化合物。
