Selective PPARδ Agonists Research Articles

Abstract 19674: Late Endothelial Progenitor Cells (EPCs) and Platelets Interact through Endothelial Differentiation Gene (Edg)-2-Lysophosphatidic Acid (LPA) Axis under the Regulation of Peroxisome Proliferator-Activated Receptor (PPAR)-δ, Leading to Vasculogenesis

Background PPAR-δ has been implicated in various cellular metabolism, but the roles in vascular biology are largely unexplored. Here, we investigated the effects of PPAR-δ activation on late EPC-platelet network. Methods & Results GW501516 (500nM), a highly selective PPAR-δ agonist treatment enhanced BrdU incorporation to human late EPCs, and augmented their pro-vasculogenic effects such as Matrigel tube formation and scratch-wound healing dose-dependently. To reveal the mechanism, the expression level of Edg family members was screened in late EPCs after PPAR-δ activation. We found that only Edg-2 mRNA and protein expression, which is a major receptor for LPA, were specifically upregulated by GW501516. ChIP and promoter assays demonstrated the direct transcriptional regulation of Edg-2. Edg-2 is a membrane receptor for LPA which is the major lysophospholipid growth factor generated on platelet activation. GW501516 (500nM), the supernatant of activated platelets, or LPA (100nM) induced the proliferation (BrdU incorporation) of late EPCs, and enhanced their provasculogenic functions such as chemotaxis (Transwell), planar migration (scratch wound healing), and capillary tube formation (in vitro Matrigel). Co-treatment of GW501516 and the supernatant synergistically enhanced the above results, suggesting the interaction between late EPCs and platelets augmented by PPAR-δ activation. But GSK0660 (1μM, PPAR-δ antagonist) or Ki16425 (3μM, EDG-2 blocker) treatment reversed the results. In vivo Matrigel plug assay (n=4, each group), the combination of late EPCs (106/plug) and platelets robustly induced capillary formation, compared with late EPCs or platelets alone. GW501516 potentiated the interaction, leading to more capillaries. In vivo mouse skin wound model (n=4, each group), late EPCs in platelet gel enhanced the wound healing with new vessel formation, which was augmented by GW501516 , confirming the interaction in vivo. PPAR-δ or EDG-2 siRNA transfection blocked all the in vivo effects of GW501516. Conclusions Platelets and late EPCs play a key role in vascular regeneration via Edg-2 - LPA axis. PPAR-δ augments the interaction through Edg-2 upregulation, suggesting its agonist as a good therapeutic tool for vascular regeneration.

Reversal of the deleterious effects of chronic dietary HFCS-55 intake by PPAR-δ agonism correlates with impaired NLRP3 inflammasome activation

Although high-fructose corn syrup (HFCS-55) is the major sweetener in foods and soft-drinks, its potential role in the pathophysiology of diabetes and obesity (“diabesity”) remains unclear. Peroxisome-proliferator activated receptor (PPAR)-δ agonists have never been tested in models of sugar-induced metabolic abnormalities. This study was designed to evaluate (i) the metabolic and renal consequences of HFCS-55 administration (15%wt/vol in drinking water) for 30 weeks on male C57Bl6/J mice and (ii) the effects of the selective PPAR-δ agonist GW0742 (1mg/kg/day for 16 weeks) in this condition. HFCS-55 caused (i) hyperlipidemia, (ii) insulin resistance, and (iii) renal injury/inflammation. In the liver, HFCS-55 enhanced the expression of fructokinase resulting in hyperuricemia and caused abnormalities in known insulin-driven signaling events. In the kidney, HFCS-55 enhanced the expression of the NLRP3 (nucleotide-binding domain and leucine-rich-repeat-protein 3) inflammasome complex, resulting in caspase-1 activation and interleukin-1β production. All of the above effects of HFCS-55 were attenuated by the specific PPAR-δ agonist GW0742. Thus, we demonstrate for the first time that the specific PPAR-δ agonist GW0742 attenuates the metabolic abnormalities and the renal dysfunction/inflammation caused by chronic HFCS-55 exposure by preventing upregulation of fructokinase (liver) and activation of the NLRP3 inflammasome (kidney).

Abstract 3802: Effect of CS-7017, a selective PPARδ agonist, on the TGFβ/Smad-mediated enhanced cell motility of EGFR-tyrosine kinase inhibitor-resistant non-small cell lung cancer cells

Abstract Background: CS-7017, a novel selective peroxisome proliferator-activated receptor gamma (PPARδ) agonist of thiazolidinedione class, has been reported to induce morphological change and cellular differentiation as well as its antiproliferative effects. A phase II clinical trial of CS-7017 in combination with epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) erlotinib is currently ongoing in advanced non-small cell lung cancer (NSCLC) patients. Though EGFR-TKIs are effective for NSCLCs with EGFR-activating mutations, the majority of responders eventually develop acquired resistance. We have previously reported that EGFR-TKI-resistant NSCLC cells acquire enhanced cell motility via activation of TGFβ pathway. In this study, we aim to investigate the effects of CS-7017 in EGFR-TKI-resistant NSCLC cells with a focus on cell motility. Materials and Methods: Erlotinib-resistant PC-9ER and gefitinib-resistant PC-9/ZD cells, established from PC-9 NSCLC cells with EGFR-activating mutation, were used for this study and constitutive PI3K/Akt activation and the EGFR T790M mutation have been previously shown to account for the acquired resistance, respectively. Growth-inhibitory effect of CS-7017 was evaluated by MTT assay. Wound closure assay and transwell assay were performed to evaluate the cell motility. The levels of TGFβ1 and 2 secretion were quantified by ELISA. Cellular mRNA levels of TGFB1 and TGFB2 were measured by qRT-PCR. Smad- or PPARδ-mediated transcriptional activity was analyzed by luciferase assay. Effects of CS-7017 on the molecules relevant to EGFR, TGFβ and PPARδ pathways were observed by immunoblot analysis. Results: Both PC-9ER and PC-9/ZD resistant cells showed the enhanced cell motility resulting from TGFβ2-induced activation of TGFβ pathway. CS-7017 showed significant inhibitory effect on the cell motility of the resistant cells but showed no growth-inhibitory effect. Moreover, combination treatment of CS-7017 and erlotinib resulted in better inhibition of the cell motility of PC-9ER cells. CS-7017 treatment was found to suppress the TGFβ2 secretion significantly resulting from downregulation of TGFB2 at transcriptional level and attenuated Smad2 phosphorylation was observed in the resistant cells. Smad-mediated transcriptional activity was also suppressed by CS-7017 treatment. CS-7017 treatment induced PPARδ-mediated transcriptional activity in PC-9 and PC-9/ZD cells but not in PC-9ER cells, suggesting that the inhibitory effect of CS-7017 on the cell motility of PC-9ER cells may not be due to direct activation of PPARδ signaling by CS-7017. Conclusions: These results imply that CS-7017 may serve as a potential therapeutic agent to prevent metastasis in NSCLC patients who develop acquired resistance to EGFR-TKIs regardless of the types of resistance mechanisms. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 3802. doi:1538-7445.AM2012-3802

Abstract 18201: PPAR-δ Augments the Interaction Between Platelets and Late EPCs via EDG-2 Signaling Pathway, Leading to Vascular Regeneration

BACKGROUND EDG (endothelial differentiation gene)-2 is a membrane receptor for LPA (lysophosphatidic acid) which is the major lysophospholipid growth factor generated by platelet activation. We focused on the role of EDG-2 in late EPCs and its regulation by PPAR (peroxisome proliferator activated receptor)-δ. METHODS & RESULTS We confirmed the expression of EDG-2 in human late EPCs. Interestingly, EDG-2 expression was upregulated by GW501516, a highly selective PPAR-δ agonist treatment. ChIP and promoter assays showed it occurred via direct transcriptional activation. GW501516 or the supernatant of activated platelets which should contain LPA increased the proliferation (BrdU) of late EPCs, and enhanced their provasculogenic functions such as chemotaxis (Transwell), planar migration (scratch wound healing), and tube formation ( in vitro Matrigel). Co-treatment of GW501516 and the supernatant resulted in synergism. The above effects were reversed by GSK0660 (PPAR-δ antagonist) or Ki16425 (EDG-2 blocker) treatment, but not so much by PDGF neutralizing antibody. In vivo Matrigel plug assay, neither late EPCs (10^6/plug) nor activated platelets induced capillary formation. But the combination of them robustly formed capillaries filled with RBCs. GW501516 potentiated their interaction, leading to more capillaries. In a mouse carotid injury model, late EPCs (DiI tagging) showed more homing to injury site 30 minutes after operation by GW501516 treatment. IF staining confirmed their interaction with platelets (CD61). After 14 days, GW501516-treated late EPC group showed more re-endothelization (IHC for CD31) and less neointimal formation. PPAR-δ or EDG-2 siRNA transfection blocked all in vivo effects of GW501516. CONCLUSIONS Platelets and late EPCs play a key role in vascular regeneration via EDG-2 - LPA axis. PPAR-δ augments the interaction through EDG-2 upregulation, suggesting its agonist as a good therapeutic candidate for ischemic vascular disease.

Effects of the PPAR-δ agonist MBX-8025 on atherogenic dyslipidemia

Objective Determine the effects of treatment with a selective PPAR-δ agonist ± statin on plasma lipoprotein subfractions in dyslipidemic individuals. Methods Ion mobility analysis was used to measure plasma concentrations of subfractions of the full spectrum of lipoprotein particles in 166 overweight or obese dyslipidemic individuals treated with the PPAR-δ agonist MBX-8025 (50 and 100 mg/d) ± atorvastatin (20 mg/d) in an 8-week randomized parallel arm double blind placebo controlled trial. Results MBX-8025 at both doses resulted in reductions of small plus very small LDL particles and increased levels of large LDL, with a concomitant reduction in large VLDL, and an increase in LDL peak diameter. This translated to reversal of the small dense LDL phenotype (LDL pattern B) in ∼90% of the participants. Modest increases in HDL particles were confined to the smaller HDL fractions. Atorvastatin monotherapy resulted in reductions in particles across the VLDL–IDL–LDL spectrum, with a significantly smaller reduction in small and very small LDL vs. MBX-8025 100 mg/d (−24.5 ± 5.3% vs. −47.8 ± 4.9%), and, in combination with MBX-8025, a reversal of the increase in large LDL. Conclusion PPAR-δ and statin therapies have complementary effects in improving lipoprotein subfractions associated with atherogenic dyslipidemia.

Activation of Peroxisome Proliferator-Activated Receptor–δ Enhances Regenerative Capacity of Human Endothelial Progenitor Cells by Stimulating Biosynthesis of Tetrahydrobiopterin

The mechanisms underlying the regenerative capacity of endothelial progenitor cells (EPCs) are not fully understood. We hypothesized that biosynthesis of tetrahydrobiopterin is an important mechanism responsible for the stimulatory effects of peroxisome proliferator-activated receptor-δ (PPARδ) activation on regenerative function of human EPCs. Treatment of human EPCs with a selective PPARδ agonist GW501516 for 24 hours increased the levels of mRNA, protein, and enzymatic activity of GTP cyclohydrolase I (GTPCH I), as well as the production of tetrahydrobiopterin. The effects of GW501516 were mediated by suppression of PTEN expression, thereby increasing phosphorylation of AKT. The AKT signaling also mediated GW501516-induced phosphorylation of endothelial NO synthase. In addition, activation of PPARδ significantly enhanced proliferation of EPCs. This effect was abolished by the GTPCH I inhibitor, 2,4-diamino-6-hydroxypyrimidine, or genetic inactivation of GTPCH I with small interfering RNA but not by inhibition of endothelial NO synthase with N(G)-nitro-l-arginine methyl ester. Supplementation of NO did not reverse 2,4-diamino-6-hydroxypyrimidine-inhibited 5-bromodeoxyuridine incorporation. Furthermore, transplantation of human EPCs stimulated re-endothelialization in a mouse model of carotid artery injury. Pretreatment of EPCs with GW501516 significantly enhanced the ability of transplanted EPCs to repair denuded endothelium. GTPCH I-small interfering RNA transfection significantly inhibited in vivo regenerative capacity of EPCs stimulated with GW501516. Thus, in human EPCs, activation of PPARδ stimulates expression and activity of GTPCH I and biosynthesis of tetrahydrobiopterin via PTEN-AKT signaling pathway. This effect enhances the regenerative function of EPCs.

The role of selective PPARδ agonists in hepatic steatosis

The role of selective PPARδ agonists in hepatic steatosis

Discovery of isoindoline and tetrahydroisoquinoline derivatives as potent, selective PPARδ agonists

Small molecule isoindoline and tetrahydroisoquinoline derivatives have been identified as selective agonists of human peroxisome proliferator-activated receptor δ (PPARδ. Compound 18 demonstrated efficacy in a biomarker for increased fatty acid oxidation, with upregulation of pyruvate dehydrogenase kinase, isozyme 4 (PDK4) in human primary myotubes.

Synthesis and biological evaluation of N-alkylated 8-oxybenz[c]azepine derivatives as selective PPARδ agonists

We describe the discovery of small molecule benzazepine derivatives as agonists of human peroxisome proliferator-activated receptor δ (PPARδ) that displayed excellent selectivity over the PPARα and PPARγ subtypes. Compound 8 displayed good PK in the rat and efficacy in upregulation of pyruvate dehydrogenase kinase, isozyme 4 (PDK4) mRNA in human primary myotubes, a biomarker for increased fatty acid oxidation.

PPAR.BETA./.DELTA. regulates the human SIRT1 gene transcription via Sp1

NAD-dependent deacetylase SIRT1 is known to be activated by caloric restriction and is related to longevity. A natural polyphenolic compound resveratrol is also shown to increases SIRT1 activity and extends lifespan. However, the transcriptional regulation of SIRT1 gene has not completely examined in the context of metabolism. Thus, in this study, we characterized the 5' -flanking region of human SIRT1 gene. We first found that representative metabolic hormones and related factors (glucocorticoid, glucagon/cAMP, and insulin) did not show significant effect on SIRT1 gene transcription. PPARalpha and PPARgamma1 without/with their specific ligands did not have significant effect as well. In contrast, expression of PPARbeta/delta (PPARdelta markedly increased the 5' -promoter activity of SIRT1 gene, which was further amplified by the addition of GW501516, a selective PPARdelta agonist. Deletion/mutation mapping analyses failed to identify PPAR binding element but revealed the presence of canonical Sp1 binding site, which was conserved among species. The Sp1 site is functional, because Sp1 overexpresson significantly enhanced SIRT1 promoter activity, and the binding of Sp1 to the element was confirmed by EMSA and ChIP assays. Interestingly, specific Sp1 antagonist mithramycin completely abolished the PPARdelta-mediated induction of SIRT1 gene transcription. Altogether, our data suggest the predominant role of PPARdelta in the transcriptional regulation of SIRT1 gene. Furthermore, the effects of PPARdelta seem to be mediated by Sp1. We assume that, in vivo, starvation increases lipolysis-derived free fatty acid and activates PPARdelta and the resultant increase in SIRT1 expression, in addition to the activation by NAD and AMPK, facilitates the deacetylation of a variety of proteins involved in mitochondrial beta-oxidation pathway and cell survival.

Induction of metastatic gastric cancer by peroxisome proliferator-activated receptorδ activation.

Peroxisome proliferator-activated receptorδ (PPARδ) regulates a multiplicity of physiological processes associated with glucose and lipid metabolism, inflammation, and proliferation. One or more of these processes likely create risk factors associated with the ability of PPARδ agonists to promote tumorigenesis in some organs. In the present study, we describe a new gastric tumor mouse model that is dependent on the potent and highly selective PPARδ agonist GW501516 following carcinogen administration. The progression of gastric tumorigenesis was rapid as determined by magnetic resonance imaging and resulted in highly metastatic squamous cell carcinomas of the forestomach within two months. Tumorigenesis was associated with gene expression signatures indicative of cell adhesion, invasion, inflammation, and metabolism. Increased PPARδ expression in tumors correlated with increased PDK1, Akt, β-catenin, and S100A9 expression. The rapid development of metastatic gastric tumors in this model will be useful for evaluating preventive and therapeutic interventions in this disease.

A PPARdelta Agonist Reduces Amyloid Burden and Brain Inflammation in a Transgenic Mouse Model of Alzheimers Disease

Agonists of the peroxisome proliferator activated receptor gamma (PPARgamma) have been shown to reduce inflammatory responses in several animal models of neurological diseases and conditions and to reduce amyloid burden in transgenic mice expressing mutant forms of human amyloid precursor protein. However, the effects of activating the related receptor PPARdelta (PPARdelta), which is expressed at higher levels in the brain than PPARgamma, on inflammation and amyloid burden have not been explored. In this study we tested the effects of the selective PPARdelta agonist GW742 in 5xFAD mice which harbor 3 mutations in amyloid precursor protein and 2 mutations in presenilin 1, develop plaques by 5-6 weeks of age, and show robust inflammation and neuronal damage. Oral delivery of GW742 significantly reduced amyloid plaque burden in the subiculum region of 3-month old male and female 5xFAD mice. GW742 also significantly reduced astrocyte activation, suggesting anti-inflammatory effects on glia cells. The changes in plaque burden were accompanied by increased expression of the amyloid degrading enzymes neprilysin and insulin degrading enzyme, while in transfected HEK293 cells, GW742 activated a neprilysin promoter driving luciferase expression. These results suggest that, as found for some PPARgamma agonists, PPARdelta agonists can also reduce amyloid burden likely to be mediated by effects on amyloid clearance.

Discovery and SAR of para-alkylthiophenoxyacetic acids as potent and selective PPARδ agonists

Synthesis and SAR of para-alkylthiophenoxyacetic acids is described. Achiral compounds 30, 31 and 32 were identified as potent and selective PPARδ agonists.

Abstract 419: Human ApoB100/CETP Transgenic Mouse is a Useful Animal Model for Evaluation of HDL-C Elevation and Suppression of Atherosclerosis by Peroxisome Proliferator-Activated Receptor Delta Agonist

PPARδ is one of the transcription factors that regulate lipid metabolism. Recently, PPARδ agonists have been reported to induce the elevation of plasma HDL-C levels in obese mice, rhesus monkeys as well as humans, indicating their potentials as a new class of HDL-C raising agent. In addition, anti-atherosclerotic effects of PPARδ agonists were reported in LDLR-KO and ApoE-KO mice. In these mice, however, the lipoprotein profiles are greatly different from those in humans in terms of the deficiency in CETP and ApoB100, and thus the anti-inflammatory effects were regarded as a main anti-atherosclerotic mechanism of PPARδ agonists. It has been reported that human ApoB100/CETP transgenic (hApoB100/CETP-Tg) mice have similar lipoprotein profiles with humans. In this study, we used hApoB100/CETP-Tg mice placed under a western diet for evaluation of GW501516, one of the most potent and selective PPARδ agonists, in order to investigate the linkage between HDL-C elevation and anti-atherosclerotic potency. For evaluation of plasma HDL-C levels, the hApoB100/CETP-Tg mice were orally treated with GW501516 for 1 week and its potency was compared with fenofibrate, a PPARα agonist used in the clinic. For evaluation of the anti-atherosclerotic effect, the mice were orally treated with GW501516 for 18 weeks and atherosclerosis at the aortic valves was determined by cross-sectional lesion analysis. Serum lipoprotein parameters were periodically monitored and lipoprotein profiles were analyzed by FPLC method. Treatment with GW501516 resulted in significant elevation of plasma HDL-C levels with more potency compared to fenofibrate (24% and 15% elevation at 10mg/kg, respectively). Serum apoA-I was also increased by the similar ratio as HDL-C, and the particle size of HDL was not changed, suggesting that the numbers of HDL particle are increased by GW501516. Long term treatment of GW501516 (3 and 10 mg/kg) resulted in dose-dependent suppression of atherosclerosis (42 and 57% inhibition, respectively) with a strong correlation with HDL-C elevation (p<0.001). By using hApoB100/CETP-Tg mice, PPARδ was confirmed as a promising target of anti-atherosclerotic therapy as a new class of HDL-C raising agent.

The PPARδ agonist, GW501516, promotes fatty acid oxidation but has no direct effect on glucose utilisation or insulin sensitivity in rat L6 skeletal muscle cells

Peroxisome proliferator-activated receptor-delta (PPARδ) activation enhances skeletal muscle fatty acid oxidation and improves whole body glucose homeostasis and insulin sensitivity. Recently, GW501516, a selective PPARδ agonist, was reported to increase glucose uptake in human skeletal myotubes by an AMPK-dependent mechanism that may contribute to the improved glucose tolerance. Here, we demonstrate that whilst GW501516 increases expression of PGC-1α and CPT-1 and stimulates fatty-acid oxidation in L6 myotubes, it fails to enhance insulin sensitivity, AMPK activity or glucose uptake and storage. Our findings exclude sarcolemmal glucose transport as a potential target for the therapeutic action of PPARδ agonists in skeletal muscle.

Selective PPARδ agonist treatment increases skeletal muscle lipid metabolism without altering mitochondrial energy coupling: an in vivo magnetic resonance spectroscopy study

Peroxisome proliferator-activated receptor-delta (PPARdelta) activation results in upregulation of genes associated with skeletal muscle fatty acid oxidation and mitochondrial uncoupling. However, direct, noninvasive assessment of lipid metabolism and mitochondrial energy coupling in skeletal muscle following PPARdelta stimulation has not been examined. Therefore, in this study we examined the response of a selective PPARdelta agonist (GW610742X at 5 or 100 mg.kg(-1).day(-1) for 8 days) on skeletal-muscle lipid metabolism and mitochondrial coupling efficiency in rats by using in vivo magnetic resonance spectroscopy (MRS). There was a decrease in the intramyocellular lipid-to-total creatine ratio as assessed by in vivo (1)H-MRS in soleus and tibialis anterior muscles by day 7 (reduced by 49 and 46%, respectively; P < 0.01) at the high dose. Following the (1)H-MRS experiment (day 8), [1-(13)C]glucose was administered to conscious rats to assess metabolism in the soleus muscle. The relative fat-vs.-carbohydrate oxidation rate increased in a dose-dependent manner (increased by 52 and 93% in the 5 and 100 mg.kg(-1).day(-1) groups, respectively; P < 0.05). In separate experiments where mitochondrial coupling was assessed in vivo (day 7), (31)P-MRS was used to measure hindlimb ATP synthesis and (13)C-MRS was used to measure the hindlimb tricarboxylic acid cycle flux (V(tca)). There was no alteration, at either dose, in mitochondrial coupling efficiency measured as the ratio of unidirectional ATP synthesis flux to V(tca). Soleus muscle GLUT4 expression was decreased by twofold, whereas pyruvate dehydrogenase kinase 4, carnitine palmitoyl transferase 1a, and uncoupling protein 2 and 3 expression was increased by two- to threefold at the high dose (P < 0.05). In summary, these are the first noninvasive measurements illustrating a selective PPARdelta-mediated decrease in muscle lipid content that was consistent with a shift in metabolic substrate utilization from carbohydrate to lipid. However, the mitochondrial-energy coupling efficiency was not altered in the presence of increased uncoupling protein expression.

Novel selective PPARδ agonists: Optimization of activity by modification of alkynylallylic moiety

Y-shaped molecules bearing alkynylallylic moieties were found to be potent and selective PPARδ activators. The alkynylallylic moiety was synthesized from alkyn-1-ols by hydroalumination followed by a cross-coupling reaction. Series of active compounds 6 were obtained by stepwise changing the structure of the known PPARpan agonist 5 into Y-shaped compounds. The most active and selective compound, 6f, had a PPARδ potency of 0.13 μM, which is 50-fold more potent than compound 5.

Phenylpropanoic acid derivatives bearing a benzothiazole ring as PPARδ-selective agonists

To find novel PPARδ-selective agonists, we designed and synthesized phenylpropanoic acid derivatives bearing 6-substituted benzothiazoles. Optimization of this series led to the identification of a potent and selective PPARδ agonist 17. Molecular modeling suggested that compound 17 occupies the Y-shaped pocket of PPARδ appropriately.

Discovery of para-alkylthiophenoxyacetic acids as a novel series of potent and selective PPARδ agonists

A novel series of potent and selective PPARδ agonists, para-alkylthiophenoxyacetic acids, was identified. The synthesis and structure–activity relationships are described.

Synthesis and SAR of selective benzothiophene, benzofuran, and indole-based peroxisome proliferator-activated receptor δ agonists

Recent literature has suggested the benefit of selective PPARδ agonists for the treatment of atherosclerosis and other disease states associated with the metabolic syndrome. Herein we report the synthesis and structure–activity relationships of a series of novel and selective PPARδ agonists. Our search began with identification of a novel benzothiophene template which was modified by the addition of various thiazolyl, isoxazolyl, and benzyloxy-benzyl moieties. Further elucidation of the SAR led to the identification of benzofuran and indole based templates. During the course of our research, we discovered three new chemical templates with varying degrees of affinity and potency for PPARδ versus the PPARα and PPARγ subtypes.