GSK3787

GSK3787 is a selective and irreversible peroxisome proliferator-activated receptor δ (PPARδ) antagonist with pIC₅₀ of 6.6. IC50 & Target: pIC50: 6.6 (PPARδ)^[1] In Vitro: GSK3787 is identified as a potent and selective hPPARδ ligand (pIC₅₀=6.6) with no measurable affinity for hPPARα or hPPARγ (pIC₅₀ < 5) in our standard in vitro ligand displacement assay. GSK3787 is inactive against hPPARα and hPPARγ in similar functional antagonist assays. GSK3787 fails to activate the receptor in a standard hPPARδ-GAL4 chimera cell-based reporter assay. GSK3787 is a selective PPARδ antagonist with equipotent species activity against the human and mouse receptor^[1]. 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 (V_ss) following iv administration are 39±11 (mL/min)/kg and 1.7±0.4 L/kg, respectively. Following oral administration, good exposure (C_max=881±166 ng/mL, AUC_inf=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 C_max 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].