Discovery of first-in-class thiazole-based dual FFA1/PPARδ agonists as potential anti-diabetic agents
Discovery of first-in-class thiazole-based dual FFA1/PPARδ agonists as potential anti-diabetic agents
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发现一流的基于噻唑的双 FFA1/PPAR δ 激动剂作为潜在的抗糖尿病药物
DOI：
10.1016/j.ejmech.2018.12.069
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发表时间：
2019-02-15
影响因子：
6.7
通讯作者：
Zhang, Luyong
中科院分区：
文献类型：
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作者：
Li, Zheng;Chen, Yueming;Zhang, Luyong
游离脂肪酸受体1(FFA1或GPR40)和过氧化物酶体增殖物激活受体Delta(PPAR Delta)分别因其促进胰岛素分泌和促进敏感性而备受关注，这是糖尿病的两个主要特征。因此，双重FFA1/PPAR Delta激动剂可能通过激活FFA1和PPAR Delta来增加胰岛素的分泌和敏感性。在这项研究中，我们将FFA1激动剂AM-4668与PPAR Delta激动剂GW501516杂交，从而鉴定出口服生物可用双激动剂32，它显示出比其他PPAR Delta更高的选择性。此外，化合物32具有较高的血药浓度、较长的半衰期和较低的体内清除量，具有良好的药代动力学特征。在降糖试验中，双激动剂32以剂量依赖的方式增强了ob/ob小鼠对葡萄糖负荷的耐受性。我们的结果表明，双FFA1/PPAR Delta激动剂可能是治疗2型糖尿病的一种有价值的药物。(C)2018年爱思唯尔·马森SAS。版权所有。
The free fatty acid receptor 1 (FFA1 or GPR40) and peroxisome proliferator-activated receptor delta (PPAR delta) have attracted a lot of attention due to their role in promoting insulin secretion and sensibility, respectively, which are two major features of diabetes. Therefore, the dual FFA1/PPAR delta agonists would increase insulin secretion and sensibility by FFA1 and PPAR delta activation. In this study, we hybrid FFA1 agonist AM-4668 with PPAR delta agonist GW501516, leading to the identification of orally bioavailable dual agonist 32, which revealed high selectivity over other PPAR delta. Moreover, compound 32 exhibited good pharmacokinetic profiles with high plasma concentration, sustained half-life and low clearance in vivo. During the hypoglycemic test, a dual agonist 32 enhanced the tolerance of ob/ob mice for glucose loading in a dose-dependent manner. Our results suggest that dual FFA1/PPAR delta agonist could be a valuable therapy for type 2 diabetes. (C) 2018 Elsevier Masson SAS. All rights reserved.