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ACS Comb Sci. 2017 Oct 9;19(10):646-656. doi: 10.1021/acscombsci.7b00066. Epub 2017 Sep 5.

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

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Department of Chemistry and Biochemistry, Milwaukee Institute for Drug Discovery, University of Wisconsin , Milwaukee, Wisconsin 53211, United States.
NIH Chemical Genomics Center, National Center for Advancing Translational Sciences (NCATS), National Institutes of Health , Bethesda, Maryland 20892-3370, United States.


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.


GW0742; nuclear receptor; peroxisome proliferation-activated receptors; steroid receptor coactivator 2; vitamin D receptor

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