Identification and Characterization of 4-Chloro-N-(2-{[5-trifluoromethyl)-2-pyridyl]sulfonyl}ethyl)benzamide (GSK3787), a Selective and Irreversible Peroxisome Proliferator-Activated Receptor δ (PPARδ) Antagonist
Abstract
4-Chloro-N-(2-{[5-trifluoromethyl)-2-pyridyl]sulfonyl}ethyl)benzamide 3 (GSK3787) was identified as a potent and selective ligand for PPARdelta with good pharmacokinetic properties. A detailed binding study using mass spectral analysis confirmed covalent binding to Cys249 within the PPARdelta binding pocket. Gene expression studies showed that pyridylsulfone 3 antagonized the transcriptional activity of PPARdelta and inhibited basal CPT1a gene transcription. Compound 3 is a PPARdelta antagonist with utility as a tool to elucidate PPARdelta cell biology and pharmacology.
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GSK3787 is a PPARδ antagonist.
“the PPARd antagonist GSK3787 (Shearer et al., 2010)”
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Targeting Peroxisome Proliferator-Activated Receptors (PPARs): Development of Modulators
Pirat, C., Farce, A., Lebègue, N., Renault, N., Furman, C., Millet, R., Yous, S., Speca, S., Berthelot, P., Desreumaux, P., et al. (2012) · Journal of Medicinal Chemistry · doi:10.1021/jm101360s · Cited by 198 · see citing works
Schubert, M., Becher, S., Wallert, M., Maeß, M. B., Abhari, M., Rennert, K., Mosig, A. S., Große, S., Heller, R., Grün, M., et al. (2020) · Molecular Pharmacology · doi:10.1124/mol.119.117887 · Cited by 35 · see citing works
- Authors
- Shearer, B. G., Wiethe, R. W., Ashe, A., Billin, A. N., Way, J. M., Stanley, T. B., Wagner, C. D., Xu, R. X., Leesnitzer, L. M., Merrihew, R. V., Shearer, T. W., Jeune, M. R., Ulrich, J. C., & Willson, T. M.
- Affiliations
- GlaxoSmithKline (United States) (US)
- Department of Metabolic Chemistry
- Discovery Technology Group
- Department of Analytical Biochemistry and Biophysics
- Department of Computational and Structural Sciences
- Department of Screening and Compound Profiling
- Department of Drug Metabolism and Pharmacokinetics
- Discovery Medicinal Chemistry
- Corresponding author
- Shearer, Barry G.
- Venue
- Journal of Medicinal Chemistry
- Publisher
- American Chemical Society (ACS)
- Published
- 2010-02-03
- Volume
- 53
- Issue
- 4
- Pages
- 1857-1861
- ISSN
- 0022-2623 (ISSN-L)
- 1520-4804
- OpenAlex
- W2063464658
- Cited by
- 78
- References
- 0
- Citations by year
- 2026: 3 · 2025: 3 · 2024: 10 · 2023: 3 · 2022: 3 · 2021: 2 · 2020: 5 · 2019: 4 · 2018: 4 · 2017: 5 · 2016: 7 · 2015: 8 · 2014: 2 · 2013: 3 · 2012: 7
- FWCI
- 3.00
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Journal of Medicinal Chemistry (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Peroxisome Proliferator-Activated Receptors
- Physical Sciences › Computer Science › Computational Theory and Mathematics › Computational Drug Discovery Methods
- Physical Sciences › Chemistry › Organic Chemistry › Synthesis and biological activity
- Keywords
- PPARδ, covalent binding, benzamide, CPT1A, transcriptional activity inhibition, pharmacokinetics, ligand identification
- MeSH terms
- Pyruvate Dehydrogenase Acetyl-Transferring Kinase, Animals, Antineoplastic Agents, Benzamides, Binding Sites, Carnitine O-Palmitoyltransferase, Cysteine, Drug Screening Assays, Antitumor, Humans, Ligands, Male, Mice, Inbred C57BL, Mass Spectrometry, Structure-Activity Relationship, Sulfones, Tissue Distribution, Transcription, Genetic, Protein Serine-Threonine Kinases, Genes, Reporter, Muscle Fibers, Skeletal, Cell Line, Tumor, PPAR delta, Mice
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