Identification and characterization of 4-chloro-N-(2-{[5-trifluoromethyl)-2-pyridyl]sulfonyl}ethyl)benzamide (GSK3787), a selective and irreversible peroxisome proliferator-activated receptor delta (PPARdelta) antagonist.

Journal of medicinal chemistry ·Vol. 53 ·No. 4 ·2010-02-25 ·Pages 1857-61

Shearer BG, Wiethe RW, Ashe A, Billin AN, Way JM, Stanley TB, Wagner CD, Xu RX, Leesnitzer LM, Merrihew RV, Shearer TW, Jeune MR, Ulrich JC, Willson TM

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.

MeSH Terms

Animals Antineoplastic Agents/chemical synthesis,pharmacokinetics,pharmacology Benzamides/chemical synthesis,pharmacokinetics,pharmacology Binding Sites Carnitine O-Palmitoyltransferase/biosynthesis,genetics Cell Line, Tumor Cysteine/metabolism Drug Screening Assays, Antitumor Genes, Reporter Humans Ligands Male Mass Spectrometry Mice Mice, Inbred C57BL Muscle Fibers, Skeletal/drug effects,enzymology PPAR delta/agonists,antagonists & inhibitors,genetics Protein Serine-Threonine Kinases/biosynthesis,genetics Pyruvate Dehydrogenase Acetyl-Transferring Kinase Structure-Activity Relationship Sulfones/chemical synthesis,pharmacokinetics,pharmacology Tissue Distribution Transcription, Genetic/drug effects

Chemicals

4-chloro-N-(2-((5-trifluoromethyl-2-pyridyl)sulfonyl)ethyl)benzamide Antineoplastic Agents Benzamides Ligands PPAR delta Pyruvate Dehydrogenase Acetyl-Transferring Kinase Sulfones Carnitine O-Palmitoyltransferase Protein Serine-Threonine Kinases Cysteine

Authors & Affiliations

14 authors, click to expand affiliations / ORCID

Shearer Barry G

Department of Metabolic Chemistry, Metabolic Diseases Centre of Excellence for Drug Discovery, GlaxoSmithKline, 5 Moore Drive, Research Triangle Park, North Carolina 27709, USA. [email protected]

Wiethe Robert W

Ashe Adam

Billin Andrew N

Way James M

Stanley Thomas B

Wagner Craig D

Xu Robert X

Leesnitzer Lisa M

Merrihew Raymond V

Shearer Todd W

Jeune Michael R

Ulrich John C

Willson Timothy M

Article Info

Journal

Journal of medicinal chemistry

Abbr.

J Med Chem

ISSN

1520-4804

DOI

10.1021/jm900464j

[email protected]

Published

2010-02-25

Pages

1857-61

Language

English

Region

United States

NLM ID

9716531

Subset

External Links

PubMed source DOI: 10.1021/jm900464j View journal details

Analysis Services

Identification and characterization of 4-chloro-N-(2-{[5-trifluoromethyl)-2-pyridyl]sulfonyl}ethyl)benzamide (GSK3787), a selective and irreversible peroxisome proliferator-activated receptor delta (PPARdelta) antagonist.

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