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首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >Scaffold-based Discovery Of Indeglitazar, A Ppar Pan-active Anti-diabetic Agent
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Scaffold-based Discovery Of Indeglitazar, A Ppar Pan-active Anti-diabetic Agent

机译：基于支架的Inparlitazar（一种Ppar泛活性抗糖尿病药）的发现

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摘要

In a search for more effective anti-diabetic treatment, we used a process coupling low-affinity biochemical screening with high-throughput co-crystallography in the design of a series of compounds that selectively modulate the activities of all three perox-isome proliferator-activated receptors (PPARs), PPARα, PPARγ, and PPARδ. Transcriptional transactivation assays were used to select compounds from this chemical series with a bias toward partial agonism toward PPARγ, to circumvent the clinically observed side effects of full PPARγ agonists. Co-crystallographic characterization of the lead molecule, indeglitazar, in complex with each of the 3 PPARs revealed the structural basis for its PPAR pan-activity and its partial agonistic response toward PPARγ. Compared with full PPARγ-agonists, indeglitazar is less potent in promoting adipocyte differentiation and only partially effective in stimulating adiponec-tin gene expression. Evaluation of the compound in vivo confirmed the reduced adiponectin response in animal models of obesity and diabetes while revealing strong beneficial effects on glucose, triglycerides, cholesterol, body weight, and other metabolic parameters. Indeglitazar has now progressed to Phase Ⅱ clinical evaluations for Type 2 diabetes mellitus (T2DM).
机译：为了寻求更有效的抗糖尿病治疗方法，我们在设计一系列化合物的过程中采用了低亲和力生化筛选与高通量共结晶相结合的方法，该化合物选择性调节所有三种过氧化物酶体增殖物激活的活性受体（PPAR），PPARα，PPARγ和PPARδ。转录反式激活法用于从该化学系列中选择对PPARγ的部分激动有偏倚的化合物，以规避临床上观察到的全PPARγ激动剂的副作用。铅分子indeglitazar与3种PPAR的复合物的共晶体学表征揭示了其PPAR泛活性及其对PPARγ的部分激动反应的结构基础。与完全PPARγ激动剂相比，茚地那扎在促进脂肪细胞分化方面作用较弱，而在刺激脂联素基因表达方面仅部分有效。体内化合物的评估证实，在肥胖和糖尿病动物模型中脂联素反应降低，同时显示出对葡萄糖，甘油三酸酯，胆固醇，体重和其他代谢参数的强大有益作用。 Indeglitazar目前已进入2型糖尿病（T2DM）的Ⅱ期临床评估。

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