Identification and Characterization of a Selective Peroxisome Proliferator-Activated Receptor β/δ (NR1C2) Antagonist

Abstract

The identification of small molecule ligands for the peroxisome proliferator-activated receptors (PPARs) has been instrumental in elucidating their biological roles. In particular, agonists have been the focus of much of the research in the field with relatively few antagonists being described and all of those being selective for PPARalpha or PPARgamma. The comparison of these agonist and antagonist ligands in cellular and animal systems has often led to surprising results and new insights into the biology of the PPARs. The PPARbeta/delta receptor is emerging as an important regulator of energy metabolism, inflammation, and cell growth and differentiation; however, only agonist ligands have been described for this receptor thus far. Here we describe the first report of a PPARbeta/delta small molecule antagonist ligand. This antagonist ligand will be a useful tool for elucidating the biological roles of PPARbeta/delta.

PPAR Agonism as New Pharmacological Approach to the Management of Acute Ischemic Stroke

“…As yet only one selective PPAR / antagonist has been described GSK0660. In skeletal muscle myoblast cells in culture, GSK0660 inhibited GW0742 induction of established PPAR / target genes (carnitine palmitoyltransferase 1A, angiopoietin-like 4 protein and pyruvate dehydrogenase kinase-4) (Shearer, Steger et al 2008). …”

Knowledge-Based Discovery of Anti-Fibrotic and Pro-Fibrotic Activities from Chinese Materia Medica

“…IN-1130, a selective inhibitor of TGF- type I receptor (Alk5), was a kind gift from Dr Dae Kee Kim, Ewha Women's University, Korea, and was used as a positive control for in vitro anti-fibrotic activity (Moon et al, 2006). Peroxisome proliferator-activated receptor (PPAR) antagonists, including PPAR antagonist GW6471 (Xu et al, 2002), PPAR/ antagonist GSK0660 (Shearer et al, 2008) and PPAR antagonist T0070907 (Lee et al, 2002) were purchased from Sigma-Aldrich.…”

“…In order to www.intechopen.com determine if the agonistic effect of SLH extract has an impact on TGF-1-induced fibrogenesis, cells were treated with SLH extract and individual PPAR antagonists. PPAR/ antagonist, GSK0660 (IC 50 160 nM) (Shearer et al, 2008), did not affect the anti-fibrotic activity of SLH extract at all concentrations tested (up to 6.25-fold higher than its IC 50 ); PPAR antagonist, GW6471 (IC 50 240 nM) (Xu et al, 2002), also did not show any significant effect at concentrations up to 4.2-fold of its IC 50 , but at 10 M (42-fold higher than its IC 50 ), it did moderately suppress the anti-fibrotic activity of SLH extract; PPAR antagonist, T0070907 (IC 50 1 nM in inhibiting rosiglitazone binding to PPAR and 3.2-24.3 μM in inhibiting proliferation of different cancer cell lines) (Lee et al, 2002;Burton et al, 2007), did not show any significant effect at concentrations of 0.1, 1 and 10 μM, but further increased the anti-fibrotic effect of SLH extract at 25 μM (Fig. 4b).…”

Synthesis, biological evaluation and molecular modeling studies of the PPARβ/δ antagonist CC618

“…The antagonistic properties of GSK0660 (4) were established through the observation of downregulation of GW501516-induced transcription of bona fide PPARβ/δ target genes. However, due to rapid clearance in rodents, GSK06660 (4) was not suited for further in vivo studies [18]. Later, Müller and coworkers used GSK0660 (4) as a lead-compound for structure-activity studies leading to e.g.…”