Novel Dual-Acting Peroxisome Proliferator-Activated Receptor Alpha and Gamma AgonistsCorrespondence Address :
Dr. Rashmi Sharma, R/O 216-A, Last-Morh Gandhi-Nagar, Near Govt Flats, Jammu (Tawi) J&K (India), Pin 180004. Email: email@example.com, firstname.lastname@example.org
Peroxisome proliferator-activated receptors (PPARs) are nuclear transcription factors, and play a central role in insulin sensitivity, lipid metabolism, and inflammation. PPAR -γ appears to improve glycaemic control by increasing peripheral insulin sensitivity and reducing hepatic glucose production, thereby helping to preserve beta-cell function. However, they have modest beneficial effects on lipid parameters. It has been observed that fibrate drugs which activate PPAR- α, produce significant improvements in dyslipidaemia and decrease atherosclerotic lesions, but do not affect glycaemia. Theoretically, a compound targeting both the α and γ PPARs simultaneously, might combine the benefits of thiazolidinediones (TZDs) and fibrates. Hence, there is a resurgence of interest in the development of new antidiabetic drugs that combine the insulin-sensitizing effects of PPARγ activation with the additional lipid-modifying activity of the other PPAR subtypes. Muraglitazar, Tesaglitazar, Ragaglitazar, Isohumulone, Farglitazar, and Naveglitazar are on the deck in late-stage clinical trials, and may be effective in reducing cardiovascular risk, but their long-term clinical effects are still unknown. The ongoing basic studies have elucidated the cardio protective role of PPAR delta. Therefore, further studies are on the track to develop PPA α/δ and PPARγ/ δ dual agonists and PPAR α/γ/δ pan agonists for the treatment of diabetic cardiovascular complications
Muraglitazar, Tesaglitazar, Ragaglitazar, Farglitazar, Naveglitazar
Peroxisome proliferator-activated receptors (PPARs) are nuclear transcription factors, and play a central role in insulin sensitivity, lipid metabolism, and inflammation. They help in the regulation of storage and catabolism of dietary fats and glucose, adipocyte differentiation, inflammatory responses, and cancer. Each PPAR consists of three functional domains;- The N-terminal, and DNA binding and ligand binding domains. PPAR forms a heterodimer with the retinoid X receptor, which recognizes DNA sequences in the promoter region of their target genes.(1) Four forms of PPARs have been described to exist, namely; PPAR-α, PPAR-β, PPAR-γ and PPAR-δ (Table/Fig 1).(1),(2),(3)
Thiazolidinediones (TZDs) or glitazones like rosiglitazone and pioglitazone are higher affinity PPAR-γ agonists for type 2 diabetes.[4,5] Glitazones cause an increase in insulin sensitivity and produce hypoglycaemic effects by increasing fatty acid extraction by adipose tissues, shifting the energy metabolism of myocytes towards glucose consumption, up- regulating or activating molecules involved in insulin signaling and glucose uptake, producing a protective effect on pancreatic beta-cells, and inhibiting tumor necrosis factor(TNF)-α.(2) The TZDs have also been shown to have antiproliferative, anti-inflammatory, and immunomodulatory effects, with a potential role in the treatment of diabetic complications, inflammatory-proliferative diseases in non-insulin-resistant euglycaemic individuals, autoimmune, atopic and inflammatory diseases, sepsis, and reperfusion injury.(6),(7) Patients with diabetes have an increased risk for cardiovascular disease that contributes to a decreased life expectancy. Various observational and interventional studies have indicated that some insulin sensitizers appear to reduce the incidence of cardiovascular events, and improve survival.(8),(9) A randomized clinical trial in patients with advanced atherosclerosis indicates that addition of pioglitazone to therapy for hyperglycaemia, may reduce the incidence of cardiovascular events such as myocardial infarction and stroke. (8),(9)
Novel peroxisome proliferator-activated receptor alpha and gama agonists:
Search Methodology: Prominent general/internal medicine journals (MEDLINE, EMBASE, PUBMED between 2000 and 2007) were searched for review papers, and pre-clinical and clinical trials published on dual PPAR α / γ agonists. All the data was collected, and important evidences regarding therapeutic uses and pharmacology of dual PPAR α / γ agonists are summarized in the present article.
Muraglitazar (BMS-298585): Muraglitazar is a non-TZDs, oxybenzylglycine dual PPAR α / γ agonist, that is in advanced clinical development for the treatment of type 2 diabetes and its associated dyslipidemia.[8,9] It shows potent activity in vitro at human PPAR α ( effective concentration (EC50) = 320 nM) and PPAR γ (EC50) = 110 nM).(11), (12) Various animal studies have documented the beneficial effect of muraglitazar on plasma lipids, glucose metabolism, and insulin resistance.
In obese diabetic db/db mice muraglitazar treatment (0.03-50 mg/ kg/ day) for 2 weeks resulted in dose-dependent reductions of glucose, insulin, triglycerides (TG), free fatty acids (FFA), and cholesterol levels. (13) In older hyperglycaemic db/db mice, longer-term muraglitazar treatment (30 mg/kg/ day for 4 weeks) prevented time-dependent deterioration of glycaemic control and development of insulin deficiency.
The new generation of dual-action glitazars are on deck in late-stage clinical trials, and may be effective in reducing cardiovascular risk, but their long-term clinical effects are still unknown (table-2 and 3). The novel PPARγ modulating drugs like Gw0072, Mcc-555, and NC-2100, with efficacious insulin sensitizing properties and minimum potential side-effects, are also under development.(1) The ongoing basic studies have elucidated the cardio protective role of PPAR δ.(35) Therefore, further studies are on the track to develop PPAR α/ δ and PPAR γ/δ dual agonists and PPAR α/γ/δ pan agonists for the treatment of diabetic cardiovascular complications. More powerful new compounds with pan-PPAR activity and proven long-term safety should be highly effective in a clinical setting of patients, with coexisting relevant lipid and glucose metabolism disorders. These discoveries pave the way for the development of drugs for treating chronic multigenic cardiovascular and metabolic diseases, for which therapy is presently insufficient or non-existent.
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