GW6471

GW6471 completely inhibits GW409544-induced activation of PPARα with IC50 of 0.24 μM. GW6471 (0.001-10 μM) disrupts the interactions between PPAR and coactivator motifs derived from SRC-1 or CBP, but promotes the binding of the co-repressor motifs from SMRT or N-CoR. GW6471 adopts a U-shaped configuration and wraps around C276 of helix 3, destroys the integrity of the charge clamp but leaves sufficient space to accommodate the additional helical turn of the co-repressor motif in the PPAR/GW6471/SMRT complexes. GW6471 (10 μM) significantly prevents cardiomyocyte differentiation and results in the reduced expression of cardiac sarcomeric proteins (ie α-actinin, troponin-T) and specific genes (ie α-MHC, MLC2v) in a time-dependent manner through inhibiting PPARα. GW6471 (10 μM) abolishes the effect of fenofibrate (10 μM) or PPARα agonist WY14643 (50 μM), which raise levels of eNOS, NO, and BH4 in human umbilical vein endothelial cells. GW6471 (0.8 μg/μL intraplantarly injected) completely abolish the inhibitory effects of URB597 on the carrageenan-evoked expansion of receptive fields.