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Parallel Chemistry Approach to Identify Novel Nuclear Receptor Ligands Based on the GW0742 Scaffold
ACS Combinatorial Science ( IF 3.903 ) Pub Date : 2017-09-05 00:00:00 , DOI: 10.1021/acscombsci.7b00066
Kelly A. Teske 1 , Ganesha Rai 2 , Premchendar Nandhikonda 1 , Preetpal S. Sidhu 1 , Belaynesh Feleke 1 , Anton Simeonov 2 , Adam Yasgar 2 , Ajit Jadhav 2 , David J. Maloney 2 , Leggy A. Arnold 1
Affiliation  

We describe the parallel synthesis of novel analogs of GW0742, a peroxisome proliferator-activated receptor δ (PPARδ) agonist. For that purpose, modified reaction conditions were applied, such as a solid-phase palladium-catalyzed Suzuki coupling. In addition, tetrazole-based compounds were generated as a bioisostere for carboxylic acid-containing ligand GW0742. The new compounds were investigated for their ability to activate PPARδ mediated transcription and their cross-reactivity with the vitamin D receptor (VDR), another member of the nuclear receptor superfamily. We identified many potent PPARδ agonists that were less toxic than GW0742, where ∼65 of the compounds synthesized exhibited partial PPARδ activity (23–98%) with EC50 values ranging from 0.007–18.2 μM. Some ligands, such as compound 32, were more potent inhibitors of VDR-mediated transcription with significantly reduced PPARδ activity than GW0742, however, none of the ligands were completely selective for VDR inhibition over PPARδ activation of transcription.

中文翻译:

基于GW0742支架的并行化学方法识别新型核受体配体

我们描述了过氧化物酶体增殖物激活受体δ(PPARδ)激动剂GW0742的新型类似物的平行合成。为此,应用了改良的反应条件,例如固相钯催化的Suzuki偶联。另外,产生了基于四唑的化合物作为含羧酸的配体GW0742的生物等排体。研究了这些新化合物激活PPARδ介导的转录的能力以及它们与核受体超家族的另一个成员维生素D受体(VDR)的交叉反应性。我们确定了许多强效的PPARδ激动剂,其毒性低于GW0742,其中约65种合成的化合物表现出部分PPARδ活性(23–98%),EC 50值为0.007–18.2μM。一些配体,例如化合物32与GW0742相比,它们是更有效的VDR介导的转录抑制剂,具有显着降低的PPARδ活性,但是,没有一个配体对VDR抑制比对PPARδ的转录激活具有完全选择性。
更新日期:2017-09-06
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