www.aladdin-e.com Address:800 S Wineville Avenue, Ontario, CA 91761,USA Website:www.aladdin-e.com Email USA: [email protected] Email EU: [email protected] Email Asia Pacific: [email protected]

Peroxisome proliferator activated receptors

Peroxisome proliferator activated receptors tissues during development especially in the (PPARs) are members of the nuclear hormone adult rat digestive tract where a high rate of cell receptor superfamily of ligand-activated renewal and differentiation is required. PPARγ is transcription factors that are related to retinoid, highly expressed in adipose tissue and is a key steroid and thyroid hormone receptors. PPARs transcription factor involved in the terminal play an important role in many cellular functions differentiation of white and brown adipose tissue. including lipid metabolism, cell proliferation, There is evidence that both PPARα and PPARγ differentiation, adipogenesis and inflammatory could interfere with atherogenesis, in part by signalling. PPARs have been found to interact exerting an anti-inflammatory activity. with a number of endogenous lipids and drugs for the treatment of human metabolic diseases. PPARs regulate gene expression by heterodimeric partnering with retinoid X receptors There are three distinct PPAR subtypes which (RXR) and subsequent binding to specific are the products of different genes and are response elements (PPREs) in the promoter commonly designated PPARα [NR1C1], PPARδ regions of target genes. Structurally distinct (also known as PPARβ and NUC1) [NR1C2] and PPREs are recognized by PPARα, δ and γ. PPARγ [NR1C3]. Each receptor shows a PPAR-RXR heterodimers can also be activated differential pattern of tissue expression and is by ligand binding to either receptor partner activated by structurally diverse compounds independently. including endogenous long-chain fatty acids. PPARs have a highly conserved DNA binding A greater understanding of the mechanism of domain (region C) and a diverse ligand- transcriptional regulation by nuclear receptors independent activation domain (region A/B) has lead to the identification of multiple which can confer constitutive activity on the accessory proteins that bind to the nuclear receptor. The C-terminal ligand-binding domain receptors in a ligand-dependent manner. The (regions E/F) is the site of ligand docking and has nuclear receptor corepressor (N-CoR) or the most diversity between the pharmacologically silencing mediator of retinoid and thyroid distinct subtypes. X-ray crystallography of human receptors (SMRT) proteins bind and mediate PPAR isoforms has revealed important residues repression of transcription by the unliganded responsible for ligand binding, heterodimerisation receptors. Coactivator proteins such as SRC1 and co-factor interactions. and CBP/p300 are recruited by agonist bound receptors and promote initiation of transcription PPARα is expressed in tissues exhibiting high by remodelling the chromatin structure while rates of β-oxidation such as liver, kidney, heart coactivators such as the PPAR binding protein and muscle. In liver, PPARα regulates lipid (PBP) and TRAP220 interact directly with the metabolism and in rodents, but not in man, transcriptional machinery. The binding of ligand PPARα activation induces hepatomegaly and triggers a series of events which result in proliferation of liver peroxisomes. PPARδ is conformational changes involving recruitment of ubiquitously expressed in tissues and has been coactivators and dissociation of corepressors. implicated in energy metabolism in both adipose The tissue specific expression of these cofactors and skeletal muscle. PPARδ is abundant in many may be responsible for the differential

1

www.aladdin-e.com

transcriptional regulation and responses the treatment of cancer, inflammation, psoriasis, observed in different cell types in vivo. atherosclerosis, dyslipidaemia, neurological disorders, obesity and diabetes. PPARα agonists (fibrates) have shown therapeutic utility as lipid lowering agents The Table below contains accepted modulators whereas PPARγ agonists such as the glitazones and additional information. For more information (thiazolidinediones) are marketed as antidiabetic and a complete list of the related products, please agents. With the involvement of PPARs in many click: Aladdin diverse metabolic pathways there is great clinical interest in the potential utility of PPAR ligands for

Currently Accepted Name PPARα PPARδ PPARγ

NR1C2 PPARβ Other Names NR1C1 NR1C3 NUC1 FAAR

440 aa (mouse) Structural 475 aa (mouse) 468 aa (mouse and human) 441 aa (human) Information 475 aa (human γ1) 506 aa (human γ2)

Adipose tissue Liver Placenta Skeletal muscle Tissue Kidney Skeletal muscle (ubiquitously Heart Expression Heart expressed) Lung Muscle Ovary

Fatty acid synthesis Physiological Fatty acid oxidation Adipocyte differentiation Oxidation Effects Cell cycle control Glucose homeostasis Ketogenesis

Diabetes Dyslipidaemia Disease Metabolic syndrome Psoriasis Atherosclerosis Relevance Cancer Cancer Inflammation Inflammation

15-Deoxy-Δ12, 14 PGJ2 azPC Ciglitazone Troglitazone (CS-045) 8(S)HETE Pioglitazone (AD-4833) LTB 4 Rosiglitazone (BRL-49653) Tetradecylthioacetic acid (TTA) LY171883 Wy-14643 L-805645 Clofibrate Prostaglandin A2 b JTT-501 Subtype Fenofibrate L-16504 AD-5075 Selective GW9578 L-631033 a L-764406 Agonists GW7647 GW501516 CLX-0921 Merck Compound 12 GW0742 KRP-297 KCL 1998001079 Farglitazar (GI262570) LY518674 GW1929 LY6487 GW7845 NNC 61-3058 GW0207 CDDO PAT5A Glycyrin

L-796449 L-796449 L-796449 Non Selective LY465608 LY465608 LY465608 Ligands c c c Bezafibrate Bezafibrate Bezafibrate

SB-213068 SB-213068 PPAR α/γ SB-219994 SB-219994 Selective LY1099 LY1099

2

www.aladdin-e.com

Ligands AZ242 (Tesaglitazar, Galida) AZ242 (Tesaglitazar, Galida) BMS298585 (Muraglitazar) BMS298585 (Muraglitazar) 9-HODE 9-HODE 13-HODE 13-HODE GW2331 GW2331 NNC 61-0029 ((-) DRF-2725, NNC 61-0029 ((-) DRF 2725, Ragaglitazar) Ragaglitazar) NNC 61-4424 NNC 61-4424 NNC 61-4718 NNC 61-4718 NNC 61-4705 NNC 61-4705 PPAR α/Δ GW2433 GW-2433 Not Known Selective Ligand Partial Agonists NC-2100 Netoglitazone MCC-555 FMOC-leucine Agonist LG100754 k Antagonists Partial Agonists Antagonist Antagonist LG100641 and Antagonists GW6471 Sulindac (NSAID)d PD068235 GW0072e BADGE f L-764406g GW9662 g T0070907 i SR-202 (Mifobate) j Diclofenac l PGC-1 PGC-1 CBP PGC-2 Coactivators CREB-binding protein/p300 SRC-2 SRC-1 ( NCoA-1) interacting transactivator with PBP (DRIP205/ TRAP220) ED-rich tail 2 N-CoR Corepressors Not Known SMRT/TRAC-2 SMRT RIP140 Interacting TRAP100 h TRAP220 RIP140 Proteins DRIP TRAP100 [3H]-BRL-49653 (rosiglitazone) [3H]-GW 2331 [3H]-GW 2433 [125I]-SB-236636 Radioligands 125 3 3 [ I]-SB-236636 [ H]-L-783483 [ H]-GW 2331 [3H]-AD-5075

Footnotes j) Decreased SRC-1 recruitment. a) This data is compiled from multiple literature k) RXR/PPARγ agonist. and from different human assays - binding l) Antagonist but can also act as a partial agonist assays and transactivation assays. Many compounds are known agonists at multiple Abbreviations PPARs with different isoform selectivities. 8(S)HETE: 8(S) Hydroxyeicosa-tetraenoic acid Selectivity > 5 fold unless indicated otherwise. 9-HODE: 9-Hydroxy-octadecadienoic acid b) L-165041 has 2.6-fold selectivity for murine 13-HODE: 13-Hydroxy-octadecadienoic acid PPARδ/PPARγ but is 10-fold selective for human azPC:Hexadecyl azelaoyl phosphatidylcholine PPARδ/PPARγ and PPARα. BADGE: Bisphenol A diglycidyl ether CBP: c) Human PPARδ/PPARα 2.5 fold selectivity and CREB-binding protein murine PPARδ/PPARγ selectivity 2-fold. CDDO: 2-Cyano-3,12-dioxooleana-1,9-dien-28- d) Antagonist activity of compound under review. oic acid e) Antagonist but partial agonist in transactivation DRIP: Vitamin D receptor-interacting proteins assays but inhibitor of adipocyte differentiation. LTB4: Leukotriene B-4 Has reduced ability to recruit coactivators to the N-CoR: Nuclear receptor corepessor transcription complex. NSAID: Non steroidal anti inflammatory f) Antagonist inhibiting adipocyte differentiation NCoA-1: Nuclear receptor coactivator but binds to PPARγ in a binding assay. PBP: PPAR binding protein PGC: Peroxisome g) Irreversible PPARγ ligand. proliferator-activated receptor gamma coactivator h) Interaction only demonstrated in vitro. RIP: Retinoid X receptor interacting protein i) Increased NCoR recruitment. SMRT: Silencing mediator of retinoid and thyroid

3

www.aladdin-e.com receptors Leo, C. and Chen, J.D., The SRC family of nuclear SRC-1: Steroid receptor coactivator-1 receptor coactivators., Gene, 245, 1-11 (2000). TRAC: Thyroid hormone receptor-associating Li, A.C. and Glass, C.K., PPAR and LXR-dependent cofactor pathways controlling lipid metabolism and the development of atherosclerosis., J. Lipid Res., 45, 2161- TRAP: Thyroid receptor-associated proteins 2173 (2004). Marx, N., et al., Peroxisome proliferator-activated References receptors and atherogenesis – regulators of gene Cheung, KF., et al., CITED2 is a novel direct effector of expression in vascular cells., Cir. Res., 94, 1168-1178 peroxisome proliferator-activated receptor γ in (2004). suppressing hepatocellular carcinoma cell growth., Miglio, G., et al., Protective effects of peroxisome Cancer., 119, 1217-1226 (2013). proliferator-activated receptor agonists on human Cipolletta, D., et al., PPAR-γ is a major driver of the podocytes: proposed mechanisms of action., Br J accumulation and phenotype of adipose tissue Treg Pharmacol., 167, 641-653 (2012). cells., Nature., 486, 549-553 (2012). Ram, V.J., Therapeutic significance of peroxisome Etgen, G.J. and Mantlo, N., PPAR ligands for metabolic proliferator-activated receptor modulators in diabetes., disorders., Curr. Topics Med. Chem., 3, 1649-1661 Drugs Today, 39, 609-632 (2003). (2003). Savkur, R.S., et al., Pharmacology of nuclear receptor- Ferre, P., The Biology of peroxisome proliferator- coregulator recognition., Vitamins and Hormones, 68, activated receptors: relationship with lipid metabolism 145-183 (2004). and insulin sensitivity., Diabetes, 53, Suppl 1 S43-S50 Wang, Y-X., et al., Regulation of muscle fiber type and (2004). running endurance by PPARδ., PLoS Biology,2, e294 Forman, B.M., et al., Hypolipidaemic drugs, (2004). polyunsaturated fatty acids, and eicosanoids are ligands Wei, W., et al., Osteoclast progenitors reside in the for peroxisome proliferator-activated receptors α and δ., peroxisome proliferator-activated receptor γ-expressing Proc. Natl. Acad. Sci.,USA, 94, 4312-4317 (1997). bone marrow cell population., Mol Cell Biol., 31, 4692- Kersten, S., et al., Roles of PPARs in health and 4705 (2011). disease., Nature, 405, 421-424 (2000). Willson, T.M, et al., The PPARs: from orphan receptors Kota, B.P., et al., An overview on biological mechanisms to drug discovery., J. Med. Chem., 43, 527-550 (2000). of PPARs, Pharmacological Res., 51, 85-94 (2005). Laghezza, A., et al., New 2-(aryloxy)-3-phenylpropanoic For more information and a complete list of the acids as peroxisome proliferator-activated receptor α/γ dual agonists able to upregulate mitochondrial carnitine related products, please click: Aladdin shuttle system gene expression., J Med Chem., 56, 60- 72 (2013).

4