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.

Cellular and Pharmacological Selectivity of the Peroxisome Proliferator-Activated Receptor-β/δ Antagonist GSK3787

“…Preliminary characterization of GSK3787 indicated that this antagonist inhibits both basal and ligand-induced expression of pyruvate dehydrogenase kinase 4 (PDK4) and carnitine palmitoyl transferase 1a (CPT1a) in human skeletal muscle cells at concentrations up to 1 M (Shearer et al, 2010). In addition, this study also demonstrated that oral administration of GSK3787 (10 mg/kg) led to a serum C max of 2.2 Ϯ 0.4 M in C57BL/6 male mice (Shearer et al, 2010).…”

“…4-[2-(3-Fluoro-4-trifluoromethyl-phenyl)-4-methyl-thiazol-5-ylmethylsulfanyl]-2-methyl-phenoxy}-acetic acid (GW0742) (Sznaidman et al, 2003), GSK0660 (Shearer et al, 2008), and GSK3787 (Shearer et al, 2010) were synthesized by GlaxoSmithKline. Acetic acid, (2-methyl-4-(((4-methyl-2-(4-(trifluoromethyl)…”

“…For mRNA analysis, cells were plated in 12-well tissue culture plates and cultured until 80% confluence, at which time they were treated with either DMSO, GW0742, GSK3787, or GW0742 and GSK3787 for 24 h. The concentrations of GW0742 (0.05-1.0 M) were used because they have been shown previously to specifically activate PPAR␤/␦ (Shearer and Hoekstra, 2003). The concentrations of GSK3787 (0.1-10 M) were used because they have been shown previously to antagonize PPAR␤/␦ in other cell-based models and are probably in the range of concentrations that could be achieved in vivo (Shearer et al, 2010). After this treatment, mRNA was isolated and used for qPCR as described above.…”

“…In contrast, the recently described PPAR␤/␦ antagonist 4-chloro-N-(2-{[5-trifluoromethyl)-2-pyridyl]sulfonyl}ethyl)benzamide (GSK3787; Fig. 1) exhibited more suitable pharmacokinetic properties, because a maximal concentration (C max ) of 2.2 Ϯ 0.4 M with a half-life of 2.5 Ϯ 1.1 h was attainable in mouse serum after oral administration (10 mg/kg) (Shearer et al, 2010). Moreover, GSK3787 is an irreversible antagonist of PPAR␤/␦ because it forms a covalent bond with a cysteine residue in the ligand binding domain of PPAR␤/␦ (Shearer et al, 2010).…”

“…1) exhibited more suitable pharmacokinetic properties, because a maximal concentration (C max ) of 2.2 Ϯ 0.4 M with a half-life of 2.5 Ϯ 1.1 h was attainable in mouse serum after oral administration (10 mg/kg) (Shearer et al, 2010). Moreover, GSK3787 is an irreversible antagonist of PPAR␤/␦ because it forms a covalent bond with a cysteine residue in the ligand binding domain of PPAR␤/␦ (Shearer et al, 2010). The present study provides further characterization of this new PPAR␤/␦ antagonist by assessing the ability of GSK3787 to antagonize PPAR␤/␦ function in vivo, examining the specificity of GSK3787 to antagonize PPAR␤/␦ using null mouse models, and by determining the effect of GSK3787 on PPAR␤/␦ function and cell growth in a panel of human cancer cell lines.…”