PPAR agonists are drugs which act upon the peroxisome proliferator-activated receptor. They are used for the treatment of symptoms of the metabolic syndrome, mainly for lowering triglycerides and blood sugar.
PPAR agonists are drugs which act upon the peroxisome proliferator-activated receptor. They are used for the treatment of symptoms of the metabolic syndrome, mainly for lowering triglycerides and blood sugar.
PPAR-alpha and PPAR-gamma are the molecular targets of a number of marketed drugs. The main classes of PPAR agonists are:
An endogenous compound, 7(S)-Hydroxydocosahexaenoic Acid (7(S)-HDHA), which is a Docosanoid derivative of the omega-3 fatty acid DHA was isolated as an endogenous high affinity ligand for PPAR-alpha in the rat and mouse brain. The 7(S) enantiomer bound with micromolar affity to PPAR alpha with 10 fold higher affinity compared to the (R) enantiomer and could trigger dendritic activation. [1] PPARα (alpha) is the main target of fibrate drugs, a class of amphipathic carboxylic acids (clofibrate, gemfibrozil, ciprofibrate, bezafibrate, and fenofibrate). They were originally indicated for dyslipidemia of cholesterol and more recently for disorders characterized by high triglycerides.
PPARγ (gamma) is the main target of the drug class of thiazolidinediones (TZDs), used in diabetes mellitus and other diseases that feature insulin resistance. It is also mildly activated by certain NSAIDs (such as ibuprofen) and indoles, as well as from a number of natural compounds. Known inhibitors include the experimental agent GW-9662.
They are also used in treating hyperlipidaemia in atherosclerosis. Here they act by increasing the expression of ABCA1, which transports extra-hepatic cholesterol into HDL. Increased uptake and excretion from the liver therefore follows.
Animal studies have shown their possible role in amelioration of pulmonary inflammation, especially in asthma. [2]
PPARδ (delta) is the main target of a research chemical named GW501516. It has been shown that agonism of PPARδ changes the body's fuel preference from glucose to lipids. [3]
A fourth class of dual PPAR agonists, so-called glitazars, which bind to both the α and γ PPAR isoforms, are currently under active investigation for treatment of a larger subset of the symptoms of the metabolic syndrome. [4] [5] These include the experimental compounds aleglitazar, muraglitazar, oxeglitazar and tesaglitazar. In June 2013, saroglitazar was the first glitazar to be approved for clinical use. [6]
In addition, there is continuing research and development of new dual α/δ and γ/δ PPAR agonists for additional therapeutic indications, as well as "pan" agonists acting on all three isoforms. [7] [8]
The anti-hypertension drug telmisartan is known to have PPAR γ/δ dual partial agonist activity in vivo. It also activates PPAR-α in vitro. [9]
A relatively recent avenue of drug research in treating depression and drug addiction is through PPARα and PPARγ activation. [10] Both TLR4-mediated and NF-κB-mediated signalling pathways have been implicated in the development of addiction to several drugs such as opioids and cocaine, and therefore are appealing targets for pharmacotherapy. [11] [12] [13] Despite a breadth of preclinical research showing potential in animal models in the treatment of drug addictions including alcohol, nicotine, cocaine, opioids and methamphetamine, the human evidence is limited with the amount of trials looking at using PPAR agonists for humans still being low; and so far (as of 2020) not being particularly promising. There are several suggested hypotheses for the poor translation from animal to human research evidence such as the potency and selectivity of PPAR ligands, sex-related variability, and species differences in the distribution and signaling of PPAR. [14]
In pharmacology, the fibrates are a class of amphipathic carboxylic acids and esters. They are derivatives of fibric acid. They are used for a range of metabolic disorders, mainly hypercholesterolemia, and are therefore hypolipidemic agents.
The thiazolidinediones, abbreviated as TZD, also known as glitazones after the prototypical drug ciglitazone, are a class of heterocyclic compounds consisting of a five-membered C3NS ring. The term usually refers to a family of drugs used in the treatment of diabetes mellitus type 2 that were introduced in the late 1990s. As of 2024, there are two FDA-approved drugs in this class, pioglitazone and rosiglitazone.
In the field of molecular biology, the peroxisome proliferator–activated receptors (PPARs) are a group of nuclear receptor proteins that function as transcription factors regulating the expression of genes. PPARs play essential roles in the regulation of cellular differentiation, development, and metabolism, and tumorigenesis of higher organisms.
Telmisartan, sold under the brand name Micardis among others, is a medication used to treat high blood pressure and heart failure. It is a reasonable initial treatment for high blood pressure. It is taken by mouth.
Bezafibrate is a fibrate drug used as a lipid-lowering agent to treat hyperlipidaemia. It helps to lower LDL cholesterol and triglyceride in the blood, and increase HDL.
Peroxisome proliferator-activated receptor gamma, also known as the glitazone reverse insulin resistance receptor, or NR1C3 is a type II nuclear receptor functioning as a transcription factor that in humans is encoded by the PPARG gene.
Obesogens are certain chemical compounds that are hypothesised to disrupt normal development and balance of lipid metabolism, which in some cases, can lead to obesity. Obesogens may be functionally defined as chemicals that inappropriately alter lipid homeostasis and fat storage, change metabolic setpoints, disrupt energy balance or modify the regulation of appetite and satiety to promote fat accumulation and obesity.
Peroxisome proliferator-activated receptor alpha (PPAR-α), also known as NR1C1, is a nuclear receptor protein functioning as a transcription factor that in humans is encoded by the PPARA gene. Together with peroxisome proliferator-activated receptor delta and peroxisome proliferator-activated receptor gamma, PPAR-alpha is part of the subfamily of peroxisome proliferator-activated receptors. It was the first member of the PPAR family to be cloned in 1990 by Stephen Green and has been identified as the nuclear receptor for a diverse class of rodent hepatocarcinogens that causes proliferation of peroxisomes.
Peroxisome proliferator-activated receptor delta(PPAR-delta), or (PPAR-beta), also known as Nuclear hormone receptor 1(NUC1) is a nuclear receptor that in humans is encoded by the PPARD gene.
Muraglitazar is a dual peroxisome proliferator-activated receptor agonist with affinity to PPARα and PPARγ.
Tesaglitazar is a dual peroxisome proliferator-activated receptor agonist with affinity to PPARα and PPARγ, proposed for the management of type 2 diabetes.
GW501516 is a PPARδ receptor agonist that was invented in a collaboration between Ligand Pharmaceuticals and GlaxoSmithKline in the 1990s. It entered into clinical development as a drug candidate for metabolic and cardiovascular diseases, but was abandoned in 2007 because animal testing showed that the drug caused cancer to develop rapidly in several organs.
Aleglitazar is a peroxisome proliferator-activated receptor agonist with affinity to PPARα and PPARγ, which was under development by Hoffmann–La Roche for the treatment of type II diabetes. It is no longer in phase III clinical trials.
Pirinixic acid is a peroxisome proliferator-activated receptor alpha (PPARα) agonist that is under experimental investigation for prevention of severe cardiac dysfunction, cardiomyopathy and heart failure as a result of lipid accumulation within cardiac myocytes. Treatment is primarily aimed at individuals with an adipose triglyceride lipase (ATGL) enzyme deficiency or mutation because of the essential PPAR protein interactions with free fatty acid monomers derived from the ATGL catalyzed lipid oxidation reaction. It was discovered as WY-14,643 in 1974.
Elafibranor (INN), sold under the brand name Iqirvo, is a medication used for the treatment of primary biliary cholangitis.
GW0742 is a PPARδ/β agonist that has been investigated for drug use by GlaxoSmithKline.
Seladelpar, sold under the brand name Livdelzi, is a medication used for the treatment of primary biliary cholangitis. It is used as the lysine dihydrate salt. It is a peroxisome proliferator-activated receptor delta (PPARδ) receptor agonist. The compound was licensed from Janssen Pharmaceutica NV.
Sodelglitazar, formerly known as GW 677954, is a thiazole PPARδ receptor agonist developed by GlaxoSmithKline. While it is primarily active at the PPARδ receptor, it is considered a pan agonist with activity at PPARα and PPARγ receptors.
Saroglitazar is a drug for the treatment of type 2 diabetes mellitus, dyslipidemia, NASH and NAFLD It is approved for use in India by the Drug Controller General of India. Saroglitazar is indicated for the treatment of diabetic dyslipidemia and hypertriglyceridemia with type 2 diabetes mellitus not controlled by statin therapy. In clinical studies, saroglitazar has demonstrated reduction of triglycerides (TG), LDL cholesterol, VLDL cholesterol, non-HDL cholesterol and an increase in HDL cholesterol a characteristic hallmark of atherogenic diabetic dyslipidemia (ADD). It has also shown anti-diabetic medication properties by reducing the fasting plasma glucose and HBA1c in diabetes patients.
A selective PPAR modulator (SPPARM) is a selective receptor modulator of the peroxisome proliferator-activated receptor (PPAR). Examples include SPPARMs of the PPARγ, BADGE, EPI-001, INT-131, MK-0533, and S26948.
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