Type-2 diabetes mellitus is a progressive cluster of metabolic disorders, representing a global public health burden affecting more than 366 million people worldwide. We recently reported the discovery of three series of novel agents showing balanced activity on two metabolic receptors, peroxisome proliferator activated receptor-γ (PPAR-γ) and free fatty acid receptor 1 (FFAR1), also known as GPCR40. Our designing strategy relied on linking the thiazolidinedione head with known GPCR privilege structures. To further investigate this concept, two new scaffolds, the benzhydrol- and indole-based chemotypes, were introduced here in. Our optimization campaign resulted in three compounds; 15a, 15c, and 15d, with affinities in the low micromolar range on both targets. In vivo study of selected test compounds, revealed that 15c possesses a significant anti-hyperglycemic and anti-hyperlipidemic activities superior to rosiglitazone in fat-fed animal models. Molecular docking analysis was conducted to explain the binding modes of both series. These compounds could lead to the development of the unique antidiabetic agent acting as insulin sensitizer as well as insulin secretagogue.

2型糖尿病是一组代谢紊乱的进行性疾病，代表着全球公共健康负担，影响着全球超过3.66亿人。我们最近报道了发现三个对两种代谢受体，过氧化物酶体增殖物激活的受体-γ（PPAR-γ）和游离脂肪酸受体1（FFAR1）（也称为GPCR40）具有平衡活性的新型药物的发现。我们的设计策略依赖于将噻唑烷二酮头与已知的GPCR特权结构联系起来。为了进一步研究这个概念，在这里引入了两种新的支架，即苯并氢基和吲哚基化学型。15a，15c和15d，在两个靶标上的亲和力均在低微摩尔范围内。在选定的测试化合物的体内研究表明，在脂肪喂养的动物模型中，15c具有明显优于罗格列酮的显着抗高血压和抗高血脂活性。进行分子对接分析以解释两个系列的结合模式。这些化合物可导致开发出独特的抗糖尿病药，用作胰岛素敏化剂和胰岛素促分泌剂。