Novel Tricyclic-α-alkyloxyphenylpropionic Acids:  Dual PPARα/γ Agonists with Hypolipidemic and Antidiabetic Activity

Sauerberg, Per; Pettersson, Ingrid; Jeppesen, Lone; Bury, Paul S.; Mogensen, John P.; Wassermann, Karsten; Brand, Christian; Sturis, Jeppe; Wöldike, H.; Fleckner, Jan; Andersen, Anne-Sofie T; Mortensen, Shila; Svensson, L. Anders; Rasmussen, Hanne B.; Lehmann, Søren Vig; Polívka, Z.; Šindelář, K.; Panajotová, Vladimíra; Ynddal, Lars; Wulff, Erik Max

doi:10.1021/jm010964g

Cited by 138 publications

(152 citation statements)

References 59 publications

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“…Recent animal studies using coagonists demonstrated combined improvements in insulin sensitivity as well as fatty acid, glucose, and lipoprotein metabolism (136,137). The PPAR␣/␥ coagonist GW2331 decreased atherosclerosis by 32% in apoE-deficient mice (84).…”

Section: Lxrsmentioning

confidence: 99%

PPAR- and LXR-dependent pathways controlling lipid metabolism and the development of atherosclerosis

Glass

2004

Journal of Lipid Research

300

180

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On June 1, 1889, 72 year old Charles-Edouard BrownSequard reported to the Societe de Biologie of Paris that he had injected himself with aqueous extracts of guinea pig and dog testes and within a short period of time experienced a remarkable enhancement in physical strength, intellectual capacity, and sexual potency (1). Brown-Sequard's self-experimentation was based on the then novel hypothesis that the testes were the source of a substance that was released into the circulation and exerted masculinizing effects on other tissues in the body. Subsequent investigation indicated that testicular extracts contain little or no active androgen, and Brown-Sequard's "rejuvination" is now considered to be a well-documented example of a placebo effect. Nevertheless, his concept of a chemical messenger was correct and greatly influenced studies of hormone-producing tissues and translational research. By 1891, Murray had successfully treated a hypothyroid patient with extracts made from the thyroid glands of sheep using Brown-Sequard's methods, representing the first example of successful hormone replacement therapy (1). Thereafter, steady progress was made in the identification and characterization of the classical steroid and thyroid hormones, which were subsequently shown to have their activity by binding to and activating so-called nuclear receptors that exerted their biological effects by regulating gene transcription. Nearly 100 years after Brown-Sequard's experiments, cDNAs encoding the glucocorticoid receptor, estrogen receptor, and thyroid hormone receptors were cloned, leading to the recognition of a superfamily of nuclear receptors that responded not only to steroid hormones but to other classes of lipid-derived mediators that function to regulate development and homeostasis (2). Here, we review recent findings that provide new insights into the roles of nuclear receptors in the control of lipid metabolism and atherosclerosis, focusing on liver X receptors (LXRs) and peroxisome proliferator-activated receptors (PPARs). Although drugs that regulate LXRs and PPARs may not have the rejuvenating properties sought by Brown-Sequard, they do hold promise for new approaches for the prevention of atherosclerosis, the leading cause of age-related morbidity and mortality in Western societies (3). PATHOGENESIS OF ATHEROSCLEROSISAtherosclerosis has its origins in pathogenic interactions between circulating lipoproteins, hemodynamic factors, the arterial wall, and the immune system. The earliest visible lesion is the "fatty streak," consisting predominantly of monocyte-derived macrophages engorged with lipoprotein-derived cholesterol (reviewed in 4).

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Section: Lxrsmentioning

confidence: 99%

PPAR- and LXR-dependent pathways controlling lipid metabolism and the development of atherosclerosis

Glass

2004

Journal of Lipid Research

300

180

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“…These doses were chosen based on their previously reported effects on atheroprotection or metabolic parameters in mice. 12,14,[22][23][24] The mice had ad libitum access to water and were weighed once per week. Blood was obtained after a 6-hour fasting period (8 AM to 2 PM) by retroorbital puncture under isoflurane-induced anesthesia or, depending on the analysis, by tail-cutting on conscious mice.…”

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confidence: 99%

PPARα, but not PPARγ, Activators Decrease Macrophage-Laden Atherosclerotic Lesions in a Nondiabetic Mouse Model of Mixed Dyslipidemia

Hennuyer

Tailleux²,

Torpier³

et al. 2005

ATVB

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Objective-Peroxisome proliferator-activated receptor (PPAR) ␣ and ␥ are nuclear receptors that may modulate atherogenesis, not only by correcting metabolic disorders predisposing to atherosclerosis but also by directly acting at the level of the vascular wall. The accumulation of lipid-laden macrophages in the arterial wall is an early pivotal event participating in the initiation and promotion of atherosclerotic lesion formation. Because PPAR␣ and ␥ modulate macrophage gene expression and cellular function, it has been suggested that their ligands may modulate atherosclerosis development via direct effects on macrophages. In this report, we investigated the effect of a PPAR␣ ligand (fenofibrate) and 2 PPAR␥ ligands (rosiglitazone and pioglitazone) on atherogenesis in a dyslipidemic nondiabetic murine model that develops essentially macrophage-laden lesions. Methods and Results-Mice were fed a Western diet supplemented or not with fenofibrate (100 mpk), rosiglitazone (10 mpk), or pioglitazone (40 mpk) for 10 weeks. Atherosclerotic lesions together with metabolic parameters were measured after treatment. Fenofibrate treatment significantly improved lipoprotein metabolism toward a less atherogenic phenotype but did not affect insulin sensitivity. Contrarily, rosiglitazone and pioglitazone improved glucose homeostasis, whereas they did not improve lipoprotein metabolism. Fenofibrate treatment significantly decreased the accumulation of lipids and macrophages in the aortic sinus. However, surprisingly, neither rosiglitazone nor pioglitazone had an effect on lesion lipid accumulation or macrophage content. Key Words: atherosclerosis Ⅲ foam cells Ⅲ peroxisome proliferator-activated receptors ␣ and ␥ Ⅲ ligands Ⅲ murine model P eroxisome proliferator-activated receptors (PPARs) are ligand-activated nuclear receptors regulating the expression of genes that control lipid and glucose homeostasis, thus modulating the major metabolic disorders predisposing to atherosclerosis. 1 Moreover, PPARs exert additional antiinflammatory and lipid-modulating effects in the arterial wall, therefore being interesting molecular targets for the treatment of atherosclerosis. 2 PPARs are the targets of 2 classes of drugs currently used in clinical practice: fibrates (fenofibrate, clofibrate, ciprofibrate, and gemfibrozil) are PPAR␣ agonists, Conclusion-These results indicate that in a dyslipidemic See page 1763whereas thiazolidinediones (TZDs) (rosiglitazone and pioglitazone) are potent PPAR␥ activators. 3 Although the beneficial effects of fibrate treatment on coronary events and atherogenesis in humans are well-documented through epidemiological and clinical intervention studies, 4 -6 results of outcome trials with PPAR␥ agonists in humans are still awaited to answer whether treatment with TZDs translates into a therapeutic benefit in atherosclerotic cardiovascular disease. The majority of clinical studies performed to date assessed the effects of TZDs in diabetic patients and most suggested vascular protective effects of PPAR␥ ligands as ...

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“…Ragaglitazar is a prototype of a new class of dual-acting peroxisome proliferator-activated receptor (PPAR)-␣ and -␥ agonists that modulate transcription activity of certain target genes involved in carbohydrate and lipid homeostasis (11)(12)(13)(14). PPAR-␣ is highly expressed in liver and muscle and upon activation leads to decreases in plasma triglycerides and increases in HDL cholesterol levels (15,16).…”

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confidence: 99%

Ragaglitazar Improves Glycemic Control and Lipid Profile in Type 2 Diabetic Subjects

Saad

Greco²,

Osei³

et al. 2004

Diabetes Care

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OBJECTIVE -Ragaglitazar is a novel insulin sensitizer with dual peroxisome proliferatoractivated receptor (PPAR)-␥ and PPAR-␣ stimulating activities that improve plasma glucose and lipid profiles. The aim of the present dose-ranging study was to assess the efficacy and safety of ragaglitazar in patients with type 2 diabetes.RESEARCH DESIGN AND METHODS -This study included 177 hypertriglyceridemic type 2 diabetic subjects who participated in a 12-week, double-blind, parallel, randomized, placebo-controlled dose-ranging study (open pioglitazone arm). Subjects received ragaglitazar (0.1, 1, 4, or 10 mg), placebo, or pioglitazone (45 mg). Efficacy parameters included fasting plasma levels of triglycerides and glucose (FPG) along with other lipid levels, A1C, and insulin.RESULTS -Ragaglitazar in doses of 1, 4, and 10 mg resulted in a significant decrease from baseline as compared with placebo in FPG (Ϫ48, Ϫ74, Ϫ77 mg/dl) and triglycerides (Ϫ40, Ϫ62, Ϫ51%), free fatty acids (Ϫ36, Ϫ54, Ϫ62%), apolipoprotein B (Ϫ13, Ϫ29, Ϫ25%), LDL cholesterol (Ϫ14 and Ϫ19% for 4-and 10-mg groups), and total cholesterol (Ϫ16 and Ϫ15% for 4 and 10 mg) and a significant increase in HDL cholesterol (20 and 31% for 1-and 4-mg groups, respectively). Changes in triglycerides and FPG for pioglitazone treatment were similar to 1 mg ragaglitazar. Mean A1C values of the 1-, 4-, and 10-mg ragaglitazar and pioglitazone groups were significantly reduced compared with placebo (Ϫ0.5, Ϫ1.3, Ϫ1.1, and Ϫ0.3%, respectively). Common adverse events were edema, weight increase, leukopenia, and anemia.CONCLUSIONS -Ragaglitazar provided glycemic control that was comparable with that of pioglitazone and, compared with placebo, provided significant improvement in the lipid profile.

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Novel Tricyclic-α-alkyloxyphenylpropionic Acids: Dual PPARα/γ Agonists with Hypolipidemic and Antidiabetic Activity

Cited by 138 publications

References 59 publications

PPAR- and LXR-dependent pathways controlling lipid metabolism and the development of atherosclerosis

PPAR- and LXR-dependent pathways controlling lipid metabolism and the development of atherosclerosis

PPARα, but not PPARγ, Activators Decrease Macrophage-Laden Atherosclerotic Lesions in a Nondiabetic Mouse Model of Mixed Dyslipidemia

Ragaglitazar Improves Glycemic Control and Lipid Profile in Type 2 Diabetic Subjects

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