| Identification | Back Directory | [Name]
4-Chloro-N-[2-[[5-(trifluoromethyl)-2-pyridinyl]sulfonyl]ethyl]benzamide | [CAS]
188591-46-0 | [Synonyms]
GSK 3787
GSK3787/GSK-3787
4-Chloro-N-(2-{[5-trifluoromethyl)-2-pyridyl]sulfonyl}ethyl)benzamide
4-Chloro-N-[2-[[5-(trifluoromethyl)-2-pyridinyl]sulfonyl]ethyl]benzamide
Benzamide, 4-chloro-N-[2-[[5-(trifluoromethyl)-2-pyridinyl]sulfonyl]ethyl]-
4-Chloro-N-[2-[[5-(trifluoromethyl)-2-pyridinyl]sulfonyl]ethyl]-benzamide GSK 3787 | [Molecular Formula]
C15H12ClF3N2O3S | [MDL Number]
MFCD00099612 | [MOL File]
188591-46-0.mol | [Molecular Weight]
393 |
| Chemical Properties | Back Directory | [Boiling point ]
585.1±50.0 °C(Predicted) | [density ]
1.448±0.06 g/cm3 (20 ºC 760 Torr) | [storage temp. ]
Store at +4°C | [solubility ]
DMSO: ≥10mg/mL | [form ]
White solid | [pka]
12.92±0.46(Predicted) | [color ]
white to off-white | [Stability:]
Stable for 1 year for up to year from date of purchase as supplied. Solutions in DMSO may be stored at -20°C for up to 3 months. | [CAS DataBase Reference]
188591-46-0 |
| Hazard Information | Back Directory | [Description]
GSK-3787 (188591-46-0) is a selective and irreversible antagonist of the peroxisome proliferator-activated receptor δ (PPARδ) – plC50 = 6.6. It covalently binds to Cys 249 in the PPARd binding site. | [Uses]
GSK3787 has been used to inhibit the role of peroxisome proliferator-activated receptor-delta (PPARδ), during the pre-implantation period of bovine embryonic development. It has also been used as a PPARδ-specific inhibitor in in vitro maturation (IVM) media to inhibit PPARδ. | [Uses]
PPARβ/δ is thought to play a role in lipid homeostasis and glucose disposal by regulating genes involved in fatty acid oxidation, reverse cholesterol transport, and carbon substrate utilization in skeletal muscle. It has also been implicated in the progression of certain cancers. GSK3787 is an irreversible antagonist of PPARβ/δ (pIC50 = 6.6) with no measurable affinity for PPARα or PPARγ (pIC50 >5). At 1μM, it inhibits the expression of PPARβ/δ-regulated target genes, pyruvate dehydrogenase kinase 4 and carnitine palmitoyl transferase 1a, which are important for energy homeostasis in human skeletal muscle cells. GSK3787 (at 1 μM) also antagonizes agonist-induced expression of angiopoietin-like protein 4 in mouse fibroblasts, mouse keratinocytes, and human MCF-7, Huh7, and HepG2 cancer cell lines.[Cayman Chemical]
| [Biochem/physiol Actions]
GSK3787 is an orally available selective irreversible Peroxisome Proliferator-Activated Receptor δ (PPARδ) antagonist (pIC50=6.6) with no measurable affinity for hPPARR or hPPARγ (pIC50<5). It acts by covalently modifying Cys249 within the ligand binding pocket, and has been shown to antagonize the induction of PPARδ-regulated target genes in skeletal muscle cells. | [in vivo]
GSK3787 has pharmacokinetic properties suitable for use as an in vivo PPARδ antagonist tool compound in mice. GSK3787 is administered intravenously (0.5 mg/kg) and orally (10 mg/kg) to male C57BL/6 mice. Mean clearance (CL) and volume of distribution at steady state (Vss) following iv administration are 39±11 (mL/min)/kg and 1.7±0.4 L/kg, respectively. Following oral administration, good exposure (Cmax=881±166 ng/mL, AUCinf=3343±332 h?ng/mL), half-life (2.7±1.1 h), and bioavailability (F=77±17%) are observed[1]. Oral administration of GSK3787 (10 mg/kg) leads to a serum Cmax of 2.2±0.4 μM in C57BL/6 male mice. Oral administration of GW0742 causes an increase in expression of Angptl4 and Adrp mRNA (known PPARβ/δ target genes) in wild-type mouse colon epithelium, and this effect is not found in Pparβ/δ-null mouse colon epithelium. Coadministration of GSK3787 with GW0742 effectively prevents the ligand-induced expression of both Angptl4 and Adrp mRNA in wild-type mouse colon epithelium, and this effect is not found in Pparβ/δ-null mouse colon epithelium. Oral administration of GSK3787 causes a modest increase in promoter occupancy of PPARβ/δ in the PPRE region of both the Angptl4 and Adrp genes, but coadministration of GSK3787 with GW0742 results in markedly less accumulation of PPARβ/δ in the PPRE region of both the Angptl4 and Adrp genes in wild-type mouse colon epithelium[2]. | [IC 50]
PPARδ: 6.6 nM (pIC50) | [storage]
Store at -20°C | [References]
Shearer et al., (2010)? 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;? J. Med. Chem.?53? 1857
Palkar?et al?(2010) Cellular and pharmacological selectivity of the peroxisome proliferator-activated receptor-β/δ antagonist GSK3787; ?Mol.Pharmacol.?78? 419 |
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