罗格列酮对过氧化物酶体增殖物激活受体γ反式抑制的构效关系
Structure-activity relationships of rosiglitazone for peroxisome proliferator-activated receptor gamma transrepression.
作者信息
Toyota Yosuke, Nomura Sayaka, Makishima Makoto, Hashimoto Yuichi, Ishikawa Minoru
机构信息
Institute of Molecular and Cellular Biosciences, The University of Tokyo, 1-1-1 Yayoi, Bunkyo-ku, Tokyo 113-0032, Japan.
Division of Biochemistry, Department of Biomedical Sciences, Nihon University School of Medicine, Itabashi-ku, Tokyo 173-8610, Japan.
出版信息
Bioorg Med Chem Lett. 2017 Jun 15;27(12):2776-2780. doi: 10.1016/j.bmcl.2017.04.061. Epub 2017 Apr 20.
Anti-inflammatory effects of peroxisome proliferator-activated receptor gamma (PPRAγ) ligands are thought to be largely due to PPARγ-mediated transrepression. Thus, transrepression-selective PPARγ ligands without agonistic activity or with only partial agonistic activity should exhibit anti-inflammatory properties with reduced side effects. Here, we investigated the structure-activity relationships (SARs) of PPARγ agonist rosiglitazone, focusing on transrepression activity. Alkenic analogs showed slightly more potent transrepression with reduced efficacy of transactivating agonistic activity. Removal of the alkyl group on the nitrogen atom improved selectivity for transrepression over transactivation. Among the synthesized compounds, 3l exhibited stronger transrepressional activity (IC: 14μM) and weaker agonistic efficacy (11%) than rosiglitazone or pioglitazone.
过氧化物酶体增殖物激活受体γ（PPRAγ）配体的抗炎作用被认为主要归因于PPARγ介导的反式抑制。因此，没有激动活性或只有部分激动活性的反式抑制选择性PPARγ配体应表现出抗炎特性且副作用减少。在此，我们研究了PPARγ激动剂罗格列酮的构效关系（SARs），重点关注反式抑制活性。烯基类似物显示出稍强的反式抑制作用，同时反式激活激动活性的效力降低。去除氮原子上的烷基提高了反式抑制相对于反式激活的选择性。在合成的化合物中，3l表现出比罗格列酮或吡格列酮更强的反式抑制活性（IC：14μM）和更弱的激动效力（11%）。
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