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Parallel Chemistry Approach to Identify Novel Nuclear Receptor Ligands Based on the GW0742 Scaffold

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...

Authors:   Kelly A. Teske; Ganesha Rai; Premchendar Nandhikonda; Preetpal S. Sidhu; Belaynesh Feleke; Anton Simeonov; Adam Yasgar; Ajit Jadhav; David J. Maloney; Leggy A. Arnold
Journal:   Journal of Combinatorial Chemistry
Year:   2017
DOI:   10.1021/acscombsci.7b00066
Publication date:   05-Sep-2017
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