Ran Yan, Pei Heying, Xie Caifeng, Ma Liang, Wu Yuzhe, Lei Kai, Shao Mingfeng, Tang Minghai, Xiang Mingli, Peng Aihua, Wei Yuquan, Chen Lijuan
State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, China.
Mol Divers. 2015 May;19(2):333-46. doi: 10.1007/s11030-015-9570-x. Epub 2015 Feb 12.
Diabetes mellitus, commonly characterized by hyperglycemia, is a group of metabolic diseases. Some oral anti-diabetic drugs show poor tolerability during chronic treatment, and associate with undesired side effects. Recent advances in the understanding of physiological functions of incretins and their degrading enzyme dipeptidyl peptidase DPP-IV have led to the discovery of DPP-IV inhibitors as a new class of oral anti-diabetic drugs. Several DPP-IV inhibitors have different chemical structures of which the xanthine scaffold has specific advantages. Combining previous work with the research strategy of pharmacophore hybridization, we retained this scaffold and synthesized a new series of amino-alcohol or diamino-modified xanthine compounds. Some xanthines exhibited submicromolar inhibitory activities against DPP-IV. The most potent compound 40 [Formula: see text] exhibits a good in vivo efficacy in reducing glucose excursion at a single dose and a better chronic effect in reducing body weight than metformin in DIO mice. In other words, the combined effect improved the pathological state of DIO mice.
糖尿病通常以高血糖为特征，是一组代谢性疾病。一些口服抗糖尿病药物在长期治疗期间耐受性较差，并伴有不良副作用。近年来，人们对肠促胰岛素及其降解酶二肽基肽酶DPP-IV的生理功能有了新的认识，从而发现了DPP-IV抑制剂作为一类新型口服抗糖尿病药物。几种DPP-IV抑制剂具有不同的化学结构，其中黄嘌呤骨架具有特定优势。结合先前的工作和药效团杂交的研究策略，我们保留了该骨架并合成了一系列新的氨基醇或二氨基修饰的黄嘌呤化合物。一些黄嘌呤对DPP-IV表现出亚微摩尔级的抑制活性。最有效的化合物40 [化学式：见正文] 在单剂量时对降低血糖波动具有良好的体内疗效，并且在DIO小鼠中比二甲双胍在减轻体重方面具有更好的长期效果。换句话说，联合作用改善了DIO小鼠的病理状态。
