当前位置：
X-MOL 学术
›
J. Med. Chem.
›
论文详情
Our official English website, www.x-mol.net, welcomes your
feedback! (Note: you will need to create a separate account there.)
Identification of the First PPARα/γ Dual Agonist Able To Bind to Canonical and Alternative Sites of PPARγ and To Inhibit Its Cdk5-Mediated Phosphorylation
Journal of Medicinal Chemistry ( IF 6.8 ) Pub Date : 2018-09-10 00:00:00 , DOI: 10.1021/acs.jmedchem.8b00835 Antonio Laghezza 1 , Luca Piemontese 1 , Carmen Cerchia 2 , Roberta Montanari 3 , Davide Capelli 3 , Marco Giudici 4 , Maurizio Crestani 4 , Paolo Tortorella 1 , Franck Peiretti 5 , Giorgio Pochetti 3 , Antonio Lavecchia 2 , Fulvio Loiodice 1
Journal of Medicinal Chemistry ( IF 6.8 ) Pub Date : 2018-09-10 00:00:00 , DOI: 10.1021/acs.jmedchem.8b00835 Antonio Laghezza 1 , Luca Piemontese 1 , Carmen Cerchia 2 , Roberta Montanari 3 , Davide Capelli 3 , Marco Giudici 4 , Maurizio Crestani 4 , Paolo Tortorella 1 , Franck Peiretti 5 , Giorgio Pochetti 3 , Antonio Lavecchia 2 , Fulvio Loiodice 1
Affiliation
|
A new series of derivatives of the PPARα/γ dual agonist 1 allowed us to identify the ligand (S)-6 as a potent partial agonist of both PPARα and γ subtypes. X-ray studies in PPARγ revealed two different binding modes of (S)-6 to the canonical site. However, (S)-6 was also able to bind an alternative site as demonstrated by transactivation assay in the presence of a canonical PPARγ antagonist and supported from docking experiments. This compound did not activate the PPARγ-dependent program of adipocyte differentiation inducing a very less severe lipid accumulation compared to rosiglitazone but increased the insulin-stimulated glucose uptake in 3T3-L1 adipocytes. Finally, (S)-6 inhibited the Cdk5-mediated phosphorylation of PPARγ at serine 273 that is currently considered the mechanism by which some PPARγ partial agonists exert antidiabetic effects similar to thiazolidinediones, without showing their typical side effects. This is the first PPARα/γ dual agonist reported to show this inhibitory effect representing the potential lead of a new class of drugs for treatment of dyslipidemic type 2 diabetes.
中文翻译：
鉴定第一个能够与PPARγ的规范位点和其他位点结合并抑制其Cdk5介导的磷酸化的PPARα/γ双激动剂
PPARα/γ双激动剂1的一系列新衍生物使我们能够将配体（S）-6鉴定为PPARα和γ亚型的有效部分激动剂。PPARγ的X射线研究显示（S）-6与典型位点的两种不同结合方式。但是，（S）-6如在典型的PPARγ拮抗剂存在下并通过对接实验支持的反式激活试验所证实的，该蛋白还能够结合一个替代位点。与罗格列酮相比，该化合物未激活脂肪细胞分化的PPARγ依赖性程序，诱导的脂质蓄积非常少，但增加了3T3-L1脂肪细胞中胰岛素刺激的葡萄糖摄取。最后，（S）-6抑制丝氨酸273上Cdk5介导的PPARγ磷酸化，目前认为该机制是一些PPARγ部分激动剂发挥类似于噻唑烷二酮的抗糖尿病作用，但未显示其典型的副作用。据报道，这是第一个显示出这种抑制作用的PPARα/γ双重激动剂，代表了新型药物治疗2型血脂异常的潜在潜力。
更新日期：2018-09-10
中文翻译：
鉴定第一个能够与PPARγ的规范位点和其他位点结合并抑制其Cdk5介导的磷酸化的PPARα/γ双激动剂
PPARα/γ双激动剂1的一系列新衍生物使我们能够将配体（S）-6鉴定为PPARα和γ亚型的有效部分激动剂。PPARγ的X射线研究显示（S）-6与典型位点的两种不同结合方式。但是，（S）-6如在典型的PPARγ拮抗剂存在下并通过对接实验支持的反式激活试验所证实的，该蛋白还能够结合一个替代位点。与罗格列酮相比，该化合物未激活脂肪细胞分化的PPARγ依赖性程序，诱导的脂质蓄积非常少，但增加了3T3-L1脂肪细胞中胰岛素刺激的葡萄糖摄取。最后，（S）-6抑制丝氨酸273上Cdk5介导的PPARγ磷酸化，目前认为该机制是一些PPARγ部分激动剂发挥类似于噻唑烷二酮的抗糖尿病作用，但未显示其典型的副作用。据报道，这是第一个显示出这种抑制作用的PPARα/γ双重激动剂，代表了新型药物治疗2型血脂异常的潜在潜力。
京公网安备 11010802027423号