The peroxisome proliferator-activated receptors (PPARs) are ligand activated transcription factors belonging to the nuclear receptor superfamily and play key roles in multiple physiological pathway. Three PPAR receptor subtypes, designated as PPARα, PPARγ, and PPARδ, have been identified. PPARδ is recognized as a regulator of genes involved in fatty acid oxidation, reverse cholesterol transport, and carbon substrate utilization in skeletal muscle. GSK3787 is a potent and selective antagonist for PPARδ with pIC50 value of 6.6 in ligand displacement assay. GSK3787 completely antagonized the activity of PPARδ agonist 1 with a pIC50 of 6.9. GSK3787 was administered to human skeletal muscle cells at various doses and found to effectively antagonize the gene expression of CPT1a. This suggests that GSK3787 may selectively block the basal activity of the receptor on some PPARδ target genes highlighting the potential utility of this compound as a useful tool for further elucidating the biological role of PPARδ. GSK3787 was 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 were 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 hng/mL), half-life (2.7 ± 1.1 h), and bioavailability (F = 77 ± 17%) were observed. Thus, GSK3787 has pharmacokinetic properties suitable for use as an in vivo PPARδ antagonist tool compound in mice[1].
作用机制
GSK3787 covalently modifies Cys249 within the ligand binding pocket[1].
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