Physiological characterization of a novel PPAR pan agonist, 2-(4-(5,6-methylenedioxybenzo[d]thiazol-2-yl)-2-methylphenoxy)-2-methylpropanoic acid (MHY2013) (original) (raw)
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Molecular Endocrinology, 2006
Partial agonists of peroxisome proliferator-activated receptor-␥ (PPAR␥), also termed selective PPAR␥ modulators, are expected to uncouple insulin sensitization from triglyceride (TG) storage in patients with type 2 diabetes mellitus. These agents shall thus avoid adverse effects, such as body weight gain, exerted by full agonists such as thiazolidinediones. In this context, we describe the identification and characterization of the isoquinoline derivative PA-082, a prototype of a novel class of non-thiazolidinedione partial PPAR␥ ligands. In a cocrystal with PPAR␥ it was bound within the ligand-binding pocket without direct contact to helix 12. The compound displayed partial agonism in biochemical and cell-based transactivation assays and caused preferential recruitment of PPAR␥-coactivator-1␣ (PGC1␣) to the receptor, a feature shared with other selective PPAR␥ modulators. It antagonized rosiglitazone-driven transactivation and TG accumulation during de novo adipogenic differentiation of murine C3H10T1/2 mesenchymal stem cells. The latter effect was mimicked by overexpression of wild-type PGC1␣ but not its LXXLLdeficient mutant. Despite failing to promote TG loading, PA-082 induced mRNAs of genes encoding components of insulin signaling and adipogenic differentiation pathways. It potentiated glucose uptake and inhibited the negative cross-talk of TNF␣ on protein kinase B (AKT) phosphorylation in mature adipocytes and HepG2 human hepatoma cells. PGC1␣ is a key regulator of energy expenditure and down-regulated in diabetics. We thus propose that selective recruitment of PGC1␣ to favorable PPAR␥-target genes provides a possible molecular mechanism whereby partial PPAR␥ agonists dissociate TG accumulation from insulin signaling. (Molecular Endocrinology 20: 809-830, 2006) P EROXISOME PROLIFERATOR-ACTIVATED RE-CEPTOR-␥ (PPAR␥) (1) is a ligand-activated transcription factor of the nuclear receptor (NR) superfamily (1). PPAR␥ forms heterodimers with the retinoid X receptor (RXR) that transactivate PPAR-responsive elements (PPREs) of target genes involved in insulin signaling, lipid/glucose metabolism, immune response, cell cycle, and differentiation of epithelial or mesenchymal cells. The receptor is selectively activated by physiological fatty acid derivatives, such as 15-deoxy-⌬ 12,14 -prostaglandin J 2 , and by a panel of chemically diverse full agonists such as glitazars and thiazolidinediones (TZDs). The TZDs rosi-and pioglitazone are insulin-sensitizing drugs approved for therapy of type 2 diabetes mellitus in humans.
PloS one, 2012
Thiazolidinediones (TZDs) act through peroxisome proliferator activated receptor (PPAR) γ to increase insulin sensitivity in type 2 diabetes (T2DM), but deleterious effects of these ligands mean that selective modulators with improved clinical profiles are needed. We obtained a crystal structure of PPARγ ligand binding domain (LBD) and found that the ligand binding pocket (LBP) is occupied by bacterial medium chain fatty acids (MCFAs). We verified that MCFAs (C8-C10) bind the PPARγ LBD in vitro and showed that they are low-potency partial agonists that display assay-specific actions relative to TZDs; they act as very weak partial agonists in transfections with PPARγ LBD, stronger partial agonists with full length PPARγ and exhibit full blockade of PPARγ phosphorylation by cyclin-dependent kinase 5 (cdk5), linked to reversal of adipose tissue insulin resistance. MCFAs that bind PPARγ also antagonize TZD-dependent adipogenesis in vitro. X-ray structure B-factor analysis and molecular ...
Expert opinion on therapeutic targets, 2017
Peroxisome proliferator-activated receptors (PPARs) are the molecular targets of hypolipidemic and insulin-sensitizing drugs and implicated in a multitude of processes that fine-tune the functions of all organs in vertebrates. As transcription factors they sense endogenous and exogenous lipid signaling molecules and convert these signals into intricate gene responses that impact health and disease. The PPARs act as modulators of cellular, organ, and systemic processes, such as lipid and carbohydrate metabolism, making them valuable for understanding body homeostasis influenced by nutrition and exercise. Areas covered: This review concentrates on synthetic and natural PPAR ligands and how they have helped reveal many aspects of the transcriptional control of complex processes important in health. Expert opinion: The three PPARs have complementary roles in the fine-tuning of most fundamental body functions, especially energy metabolism. Understanding their inter-relatedness using liga...
Selective modulators of PPAR activity as new therapeutic tools in metabolic diseases
Endocrine, metabolic & immune disorders drug targets, 2006
Peroxisome Proliferator Activated Receptors (PPARs) are regulators of metabolic pathways mainly of lipid metabolism and energy balance. Their medical importance is given by the fact that they have been implicated in development of insulin resistance, obesity and atherosclerosis. In recent years, major progress has been made in understanding the molecular basis of the function of these receptors. As a result of structural studies and identification of putative natural as well as synthetic ligands and activators of PPARs a new concept emerged and new drugs are on their ways to the clinic. The concept of Selective PPAR Modulators (SPPARM) was suggested by analogy to Selective Estrogen Receptor Modulators (SERM). SPPARMs activate the receptors in distinct ways leading to differential gene expression and biological response. The key features in understanding their action is most likely at the molecular details of ligand binding and the subsequently induced conformational changes as well ...
Metabolism-clinical and Experimental, 2008
Peroxisome proliferator-activated receptor α (PPARα) is a member of the nuclear receptor family of ligand-activated transcription factors. It plays an important role in the regulation of genes involved in lipid metabolism and transport. Compound A is a potent and orally active PPARα agonist that activated both human and rat PPARα receptors. The compound induced the expression of genes involved in fatty acid metabolism in a rodent hepatoma cell line and in the liver of db/db mouse. The ability of compound A to stimulate fatty acid β-oxidation was demonstrated in human hepatocytes and human skeletal muscle cells, which confirmed a functional activation of PPARα-mediated activities. Compound A was shown to be a more potent and efficacious antidyslipidemic agent in atherogenic rat and db/db mouse models as compared with fenofibrate. The increase in high-density lipoprotein cholesterol levels by compound A was at least partially due to an increase in serum apolipoprotein A-I protein concentrations in human PPARα transgenic mouse. The triglyceride-lowering effect was further confirmed in a higher species, obese dog models. In addition, compound A dose-dependently ameliorated hyperglycemia and hyperinsulinemia, and improved glucose tolerance in db/db mice. In a diet-induced obesity mouse model, compound A decreased body weight mainly by increasing energy expenditure and reducing fat deposition. In conclusion, the novel and potent PPARα agonist improves lipid profile, insulin sensitivity, and energy balance in animal models.
Molecular Medicine Reports, 2008
Peroxisome proliferator-activated receptors (PPARs) belong to a family of transcription factors of which three isotypes, PPARα, PPARδ (ß) and PPARγ, are known. These play a central role in regulating intermediate metabolism and in incidences of inflammation. In recent years, a greater understanding of their mechanisms of action and their effects, principally in the management of cardiovascular disease, has been achieved. PPAR agonists, catalysts and agents have been used since the 1990s, when it was confirmed that fibrates possess lipid modifying properties when selectively activating PPARα. In addition, thiazolidinediones, structures analogous to fibrates, showed PPARγ activity with an insulin-sensitizing effect, leading to their use in the control and even prevention of diabetes mellitus type 2. Currently, studies are oriented to the development of agents that activate multiple PPAR isoforms-not only dual (PPARα/γ), but also PPAR pan-agonists (α/γ/δ). The purpose of this review is to explain the mechanisms of the molecular action and the effects of PPAR agonists, and also to analyze existing and current studies concerning their use in cardiovascular and metabolic illnesses.
Treatment of Obesity-Related Complications with Novel Classes of Naturally Occurring PPAR Agonists
Journal of Obesity, 2011
The prevalence of obesity and its associated comorbidities has grown to epidemic proportions in the US and worldwide. Thus, developing safe and effective therapeutic approaches against these widespread and debilitating diseases is important and timely. Activation of peroxisome proliferator-activated receptors (PPARs) α, γ, and δ through several classes of pharmaceuticals can prevent or treat a variety of metabolic and inflammatory diseases, including type II diabetes (T2D). Thus, PPARs represent important molecular targets for developing novel and better treatments for a wide range of debilitating and widespread obesity-related diseases and disorders. However, available PPAR γ agonistic drugs such as Avandia have significant adverse side effects, including weight gain, fluid retention, hepatotoxicity, and congestive heart failure. An alternative to synthetic agonists of PPAR γ is the discovery and development of naturally occurring and safer nutraceuticals that may be dual or pan PP...