GSK3787

188591-46-0

C15H12ClF3N2O3S

DMSO : >= 50 mg/mL (127.30 mM); H2O : < 0.1 mg/mL (insoluble)

Cell Cycle/DNA Damage

GSK3787 is a selective and irreversible peroxisome proliferator-activated receptor delta (PPARdelta) antagonist with pIC₅₀ of 6.6. IC50 & Target: pIC50: 6.6 (PPARdelta)^[1] In Vitro: GSK3787 is identified as a potent and selective hPPARdelta ligand (pIC₅₀=6.6) with no measurable affinity for hPPARalpha or hPPARgamma (pIC₅₀ < 5) in our standard in vitro ligand displacement assay. GSK3787 is inactive against hPPARalpha and hPPARgamma in similar functional antagonist assays. GSK3787 fails to activate the receptor in a standard hPPARdelta-GAL4 chimera cell-based reporter assay. GSK3787 is a selective PPARdelta 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 PPARdelta 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 uM in C57BL/6 male mice. Oral administration of GW0742 causes an increase in expression of Angptl4 and Adrp mRNA (known PPARbeta/delta target genes) in wild-type mouse colon epithelium, and this effect is not found in Pparbeta/delta-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 Pparbeta/delta-null mouse colon epithelium. Oral administration of GSK3787 causes a modest increase in promoter occupancy of PPARbeta/delta in the PPRE region of both the Angptl4 and Adrp genes, but coadministration of GSK3787 with GW0742 results in markedly less accumulation of PPARbeta/delta in the PPRE region of both the Angptl4 and Adrp genes in wild-type mouse colon epithelium^[2].