- Parallel Chemistry Approach to Identify Novel Nuclear Receptor Ligands Based on the GW0742 Scaffold
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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.
- Teske, Kelly A.,Rai, Ganesha,Nandhikonda, Premchendar,Sidhu, Preetpal S.,Feleke, Belaynesh,Simeonov, Anton,Yasgar, Adam,Jadhav, Ajit,Maloney, David J.,Arnold, Leggy A.
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p. 646 - 656
(2017/10/13)
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- Medicaments
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Methods or prevention or treatment of diseases or conditions where inhibition of NO synthase and/or TNF is desirable, the use of PPAR delta activators in such methods and methods for the identification of compounds useful in such treatment.
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- Activator of PPAR delta
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Compounds of Formula (I) are disclosed. These compounds include selective activators of human PPAR delta.
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- Novel selective small molecule agonists for peroxisome proliferator-activated receptor δ (PPARδ) - Synthesis and biological activity
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We report the synthesis and biological activity of a new series of small molecule agonists of the human Peroxisome Proliferator-Activated Receptor δ (PPARδ). Several hits were identified from our original libraries containing lipophilic carboxylic acids. Optimization of these hits by structure-guided design led to 7k (GW501516) and 7l (GW0742), which shows an EC50 of 1.1 nM against PPARδ with 1000-fold selectivity over the other human subtypes.
- Sznaidman, Marcos L.,Haffner, Curt D.,Maloney, Patrick R.,Fivush, Adam,Chao, Esther,Goreham, Donna,Sierra, Michael L.,LeGrumelec, Christelle,Xu, H. Eric,Montana, Valerie G.,Lambert, Millard H.,Willson, Timothy M.,Oliver Jr., William R.,Sternbach, Daniel D.
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p. 1517 - 1521
(2007/10/03)
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