Parallel Chemistry Approach to Identify Novel Nuclear Receptor Ligands Based on the GW0742 Scaffold. ACS Comb Sci 2017 Oct 09;19(10):646-656
Date
08/22/2017Pubmed ID
28825467Pubmed Central ID
PMC5643073DOI
10.1021/acscombsci.7b00066Scopus ID
2-s2.0-85030765458 (requires institutional sign-in at Scopus site) 2 CitationsAbstract
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.
Author List
Teske KA, Rai G, Nandhikonda P, Sidhu PS, Feleke B, Simeonov A, Yasgar A, Jadhav A, Maloney DJ, Arnold LAAuthor
Alexander (Leggy) Arnold PhD Professor in the Chemistry & Biochemistry department at University of Wisconsin - MilwaukeeMESH terms used to index this publication - Major topics in bold
Cell SurvivalDrug Design
HEK293 Cells
High-Throughput Screening Assays
Humans
Ligands
Molecular Docking Simulation
PPAR delta
Receptors, Calcitriol
Small Molecule Libraries
Structure-Activity Relationship
Tetrazoles
Thiazoles
Transcription, Genetic