Enantioselective Synthesis of a Novel Thiazoline Core as a Potent Peroxisome Proliferator-Activated Receptor ? Agonist.
Ontology highlight
ABSTRACT:
SUBMITTER: Lee SJ
PROVIDER: S-EPMC6044852 | biostudies-literature | 2018 Feb
REPOSITORIES: biostudies-literature
Publications
Enantioselective Synthesis of a Novel Thiazoline Core as a Potent Peroxisome Proliferator-Activated Receptor δ Agonist.
Lee Su-Jeong SJ Samala Mallesham M Woo Seo Yeon SY Hahn Dongyup D Kim Dayoung D Kadayat Tara Man TM Jung Kyungjin K Kim Jina J Kim Dong-Su DS Kwon Sugyeong S Kim Shinae S Kim Kyung-Hee KH Nam Sang-Jip SJ Cho Sung Jin SJ Chin Jungwook J
ACS omega 20180215 2
The convergent and enantioselective synthesis of a highly potent human peroxisome proliferator-activated receptor delta agonist is presented. More specifically, the thiazoline structure, which constitutes the biosynthetically distinctive core structure of pulicatin (a secondary metabolite of symbiotic bacteria), was synthesized from a commercially available and inexpensive chiral pool of l-threonine. ...[more]
Similar Datasets
Project description:Iloprost is a prostacyclin analog that has been used to treat many vascular conditions. Peroxisome proliferator-activated receptors (PPARs) are ligand-regulated transcription factors with various important biological effects such as metabolic and cardiovascular physiology. Here, we report the crystal structures of the PPAR? ligand-binding domain and PPAR? ligand-binding domain bound to iloprost, thus providing unambiguous evidence for the direct interaction between iloprost and PPARs and a structural basis for the recognition of PPAR?/? by this prostacyclin analog. In addition to conserved contacts for all PPAR? ligands, iloprost also initiates several specific interactions with PPARs using its unique structural groups. Structural and functional studies of receptor-ligand interactions reveal strong functional correlations of the iloprost-PPAR?/? interactions as well as the molecular basis of PPAR subtype selectivity toward iloprost ligand. As such, the structural mechanism may provide a more rational template for designing novel compounds targeting PPARs with more favorable pharmacologic impact based on existing iloprost drugs.
| S-EPMC3173080 | biostudies-literature
Project description:Peroxisome proliferator-activated receptor-delta (PPAR-δ)-dependent signaling is associated with rapid wound healing in the skin. Here, we investigated the therapeutic effects of PPAR-δ-agonist treatment on cardiac healing in post-myocardial infarction (MI) rats. Animals were assigned to the following groups: sham-operated control group, left anterior descending coronary artery ligation (MI) group, or MI with administration of the PPAR-δ agonist GW610742 group. GW610742 (1 mg/kg) was administrated intraperitoneally after the operation and repeated every 3 days. Echocardiographic data showed no differences between the two groups in terms of cardiac function and remodeling until 4 weeks. However, the degrees of angiogenesis and fibrosis after MI were significantly higher in the GW610742-treated rats than in the untreated MI rats at 1 week following MI, which changes were not different at 2 weeks after MI. Naturally, PPAR-δ expression in infarcted myocardium was highest increased in 3 day after MI and then disappeared in 14 day after MI. GW610742 increased myofibroblast differentiation and transforming growth factor-beta 2 expression in the infarct zone at 7 days after MI. GW610742 also increased bone marrow-derived mesenchymal stem cell (MSC) recruitment in whole myocardium, and increased serum platelet-derived growth factor B, stromal-derived factor-1 alpha, and matrix metallopeptidase 9 levels at day 3 after MI. PPAR-δ agonists treatment have the temporal effect on early fibrosis of infarcted myocardium, which might not sustain the functional and structural beneficial effect.
| S-EPMC4749247 | biostudies-literature
Project description:Background: Very long-chain acyl-CoA dehydrogenase (VLCAD) deficiency is an autosomal recessive disease that prevents the body from utilizing long-chain fatty acids for energy, most needed during stress and fasting. Symptoms can appear from infancy through childhood and adolescence or early adulthood, and include hypoglycemia, recurrent rhabdomyolysis, myopathy, hepatopathy, and cardiomyopathy. REN001 is a peroxisome-proliferator-activated receptor delta (PPARδ) agonist that modulates the expression of the genes coding for fatty acid β-oxidation enzymes and proteins involved in oxidative phosphorylation. Here, we assessed the effect of REN001 on VLCAD-deficient patient fibroblasts. Methods: VLCAD-deficient patient and control fibroblasts were treated with REN001. Cells were harvested for gene expression analysis, protein content, VLCAD enzyme activity, cellular bioenergetics, and ATP production. Results: VLCAD-deficient cell lines responded differently to REN001 based on genotype. All cells had statistically significant increases in ACADVL gene expression. Small increases in VLCAD protein and enzyme activity were observed and were cell-line- and dose-dependent. Even with these small increases, cellular bioenergetics improved in all cell lines in the presence of REN001, as demonstrated by the oxygen consumption rate and ATP production. VLCAD-deficient cell lines containing missense mutations responded better to REN001 treatment than one containing a duplication mutation in ACADVL. Discussion: Treating VLCAD-deficient fibroblasts with the REN001 PPARδ agonist results in an increase in VLCAD protein and enzyme activity, and a decrease in cellular stress. These results establish REN001 as a potential therapy for VLCADD as enhanced expression may provide a therapeutic increase in total VLCAD activity, but suggest the need for mutation-specific treatment augmented by other treatment measures.
| S-EPMC9454759 | biostudies-literature
Project description:PPARδ is emerging as a key metabolic regulator with pleiotropic actions on various tissues including fat, skeletal muscle and liver. The aim of our study was to assess the effect of either the well-validated PPARδ agonist GW501516, or a novel PPARδ agonist KD3010 in mouse models of liver fibrosis. KD3010, but not GW501516, treated mice had markedly less liver injury induced by carbon tetrachloride (CCl4) injections. Deposition of extracellular matrix proteins was lower in the KD3010 group as compared to the vehicle or GW501516 treated group. Interestingly, profibrogenic CTGF was significantly induced by GW501516, but not KD3010, following CCl4 treatment. The hepatoprotective and antifibrotic effect of KD3010 was confirmed in a model of cholestasis-induced liver injury and fibrosis using bile duct ligation for three weeks. Hepatocytes were identified as targets for PPARδ agonist, and primary hepatocytes treated with KD3010 showed decreased serum starvation or CCl4-induced cell death, while GW501516 treated hepatocytes were not protected. KD3010 treatment of hepatocytes decreased reactive oxygen species (ROS) production after CCl4 exposure. In conclusion, our data demonstrate that a novel PPARδ agonist has hepatoprotective and antifibrotic effects in animal models of liver fibrosis. Given the oral availability and the favorable pharmacologic profile of KD3010, ligand activation of PPARδ represents an attractive and promising target for patients with chronic liver diseases.
2012-04-19 | GSE32121 | GEO
Project description:PPARδ is emerging as a key metabolic regulator with pleiotropic actions on various tissues including fat, skeletal muscle and liver. The aim of our study was to assess the effect of either the well-validated PPARδ agonist GW501516, or a novel PPARδ agonist KD3010 in mouse models of liver fibrosis. KD3010, but not GW501516, treated mice had markedly less liver injury induced by carbon tetrachloride (CCl4) injections. Deposition of extracellular matrix proteins was lower in the KD3010 group as compared to the vehicle or GW501516 treated group. Interestingly, profibrogenic CTGF was significantly induced by GW501516, but not KD3010, following CCl4 treatment. The hepatoprotective and antifibrotic effect of KD3010 was confirmed in a model of cholestasis-induced liver injury and fibrosis using bile duct ligation for three weeks. Hepatocytes were identified as targets for PPARδ agonist, and primary hepatocytes treated with KD3010 showed decreased serum starvation or CCl4-induced cell death, while GW501516 treated hepatocytes were not protected. KD3010 treatment of hepatocytes decreased reactive oxygen species (ROS) production after CCl4 exposure. In conclusion, our data demonstrate that a novel PPARδ agonist has hepatoprotective and antifibrotic effects in animal models of liver fibrosis. Given the oral availability and the favorable pharmacologic profile of KD3010, ligand activation of PPARδ represents an attractive and promising target for patients with chronic liver diseases. Total RNA was extracted from primary mouse hepatocytes treated with DMSO or PPARd agonists (KD3010, GW1516)
2012-04-18 | E-GEOD-32121 | biostudies-arrayexpress
Project description:Pulmonary hypertension is a debilitating disease with no cure. We have previously shown that peroxisome proliferator-activated receptor (PPAR) β/δ agonists protect the right heart in hypoxia-driven pulmonary hypertension without affecting vascular remodeling. PPARβ/δ is an important receptor in lipid metabolism, athletic performance, and the sensing of prostacyclin. Treatment of right heart hypertrophy and failure in pulmonary hypertension is an emerging target for future therapy. Here we have investigated the potential of GW0742, a PPARβ agonist, to act directly on the right heart in vivo and what transcriptomic signatures are associated with its actions. Right heart hypertrophy and failure was induced in mice using a pulmonary artery banding (PAB) model. GW0742 was administered throughout the study. Cardiovascular parameters were measured using echocardiography and pressure monitoring. Fibrosis and cellular changes were measured using immunohistochemistry. Transcriptomics were measured using the Illumina MouseRef-8v3 BeadChip array and analyzed using GeneSpring GX (ver. 11.0). PAB resulted in right heart hypertrophy and failure and in increased fibrosis. GW0742 reduced or prevented the effects of PAB on all parameters measured. GW0742 altered a number of genes in the transcriptome, with Angptl4 emerging as the top gene altered (increased) in animals with PAB. In conclusion, the PPARβ/δ agonist GW0742 has direct protective effects on the right heart in vivo. These observations identify PPARβ/δ as a viable therapeutic target to treat pulmonary hypertension that may complement current and future vasodilator drugs.
| S-EPMC4070821 | biostudies-literature
Project description:ContextObesity is a multifactorial disorder, that is, a disease determined by the combined effect of genes and environment. In this context, polygenic approaches are needed.ObjectiveTo investigate the possibility of the existence of a crosstalk between the CALPAIN 10 homologue CALPAIN 5 and nuclear receptors of the peroxisome proliferator-activated receptors family.DesignCross-sectional, genetic association study and gene-gene interaction analysis.SubjectsThe study sample comprise 1953 individuals, 725 obese (defined as body mass index > or = 30) and 1228 non obese subjects.ResultsIn the monogenic analysis, only the peroxisome proliferator-activated receptor delta (PPARD) gene was associated with obesity (OR = 1.43 [1.04-1.97], p = 0.027). In addition, we have found a significant interaction between CAPN5 and PPARD genes (p = 0.038) that reduces the risk for obesity in a 55%.ConclusionOur results suggest that CAPN5 and PPARD gene products may also interact in vivo.
| S-EPMC2527300 | biostudies-literature
Project description:Peroxisome Proliferator-Activated Receptor γ (PPARγ) is a nuclear receptor important for glucose homeostasis and insulin sensitivity. The anti-diabetic drugs thiazolidinediones improve insulin sensitivity by blocking PPARγ phosphorylation at S273; however, their full agonism on PPARγ also causes significant unwanted side effects. The indole derivative UHC1 displays insulin-sensitizing effect by acting as a partial agonist through the inhibition of PPARγ S273 phosphorylation, but without full agonist-associated side effects; however, its potency leaves much to be desired. Herein we report the design and synthesis of potent indole analogs as partial PPARγ agonists via the structure-activity relationship studies. Our studies revealed that vanillylamine and piperonyl benzylamine at Site 1 are favored to bind PPARγ with either biphenyl or 3-trifluoromethyl benzyl group at Site 2. In particular, compound WO91A with vanillylamine at Site 1 displays highly potent PPARγ binding affinity (IC50 = 16.7 nM), over 30-fold more potent than the parental compound UHC1, yet with less side effect-associated transactivation activity.
| S-EPMC7243741 | biostudies-literature
Project description:Liver insufficiency and damage are major causes of death and disease worldwide and may result from exposure to environmental toxicants, specific combinations or dosages of pharmaceuticals, and microbial metabolites. The generation of reactive intermediates, in particular 4-hydroxynonenal (4-HNE), is a common event in liver damage caused by a variety of hepatotoxic drugs and solvents. The peroxisome proliferator-activated receptors (PPARs) are nuclear receptors that are involved in the transcriptional regulation of lipid metabolism as well as other biological functions. Importantly, we have observed that the PPARbeta/delta-/- mouse is more susceptible to chemically induced hepatotoxicity than its wild-type counterpart, and our objective in this study was to elucidate the mechanism(s) by which PPARbeta/delta confers protection to hepatocytes. We hypothesized that PPARbeta/delta plays a protective role by responding to toxic lipids and altering gene expression accordingly. In support, oxidized-VLDL and constituents including 13-S-hydroxyoctadecadienoic acid (13-S-HODE) and 4-HNE are PPARbeta/delta ligands. A structure-activity relationship was established where 4-HNE and 4-hydroperoxynonenal (4-HpNE) enhanced the activity of the PPARbeta/delta subtype while 4-hyroxyhexenal (4-HHE), 4-oxo-2-Nonenal (4-ONE), and trans-4,5-epoxy-2(E)-decenal did not activate this receptor. Increasing PPARbeta/delta activity with a synthetic agonist decreased sensitivity of hepatocytes to 4-HNE and other toxic agents, whereas inhibition of this receptor had the opposite result. Gene expression microarray analysis identified several important PPARbeta/delta-regulated detoxification enzymes involved in 4-HNE metabolism that are regulated at the transcript level. This research established 4-HNE as an endogenous modulator of PPARbeta/delta activity and raises the possibility that agonists of this nuclear receptor may be utilized to prevent or treat liver disease associated with oxidative damage.
| S-EPMC1892209 | biostudies-literature
Project description:AimsFibrate medications weakly stimulate the nuclear receptor peroxisome proliferator-activated receptor-α (PPAR-α) and are currently employed clinically in patients with dyslipidaemia. The potent and selective agonist of PPAR-α LY518674 is known to substantially increase apolipoprotein A-I (apoA-I) turnover without major impact on steady-state levels of apoA-I or high-density lipoprotein-cholesterol (HDL-C). We sought to determine whether therapy with a PPAR-α agonist impacts cholesterol efflux capacity, a marker of HDL function.Methods and resultsCholesterol efflux capacity was measured at baseline and after 8 weeks of therapy in a randomized, placebo-controlled trial involving participants with metabolic syndrome treated with either LY518674 100 μg daily (n = 13) or placebo (n = 15). Efflux capacity assessment was quantified using a previously validated ex vivo assay that measures the ability of apolipoprotein-B depleted plasma to mobilize cholesterol from macrophages. LY518674 led to a 15.7% increase from baseline (95% CI 3.3-28.1%; P = 0.02, P vs. placebo = 0.01) in efflux capacity. The change in apoA-I production rate in the active treatment arm was strongly linked to change in cholesterol efflux capacity (r = 0.67, P = 0.01).ConclusionsPotent stimulation of PPAR-α leads to accelerated turnover of apoA-I and an increase in cholesterol efflux capacity in metabolic syndrome patients despite no change in HDL-C or apoA-I levels. This finding reinforces the notion that changes in HDL-C levels may poorly predict impact on functionality and thus has implications for ongoing pharmacologic efforts to enhance apoA-I metabolism.
| S-EPMC4644252 | biostudies-literature