Review Article Current Pharma Research ISSN: 2230-7842 CPR 3(2), 2013, 846-854.

PPAR Dual Agonist: In Treatment of Type II Diabetes.

*1Kishan Patel, 1R. N. Sharma, 1L. J. Patel, 2G. M. Patel 1S. K. Patel College of Pharmaceutical Education and Research, Ganpat University, Mehsana-Gozaria Highway, Kherva, Gujarat, India, 2K. B. Institute of Pharmaceutical Education and Research, Gandhinagar, Gujarat, India.

Abstract Peroxisome proliferator-activated receptors (PPARs) are central regulators of lipoprotein metabolism and glucose homeostasis that are considered particularly useful for improving glycemic control and co morbidities in patients with type II diabetes mellitus. Clinical trials of PPAR-α agonists have demonstrated efficacy in reducing cardiovascular events; however, these benefits have been confined to subgroups of patients with low levels of high-density lipoprotein cholesterol or high levels of triglycerides. While activators of PPAR-γ reduce early atherosclerotic lesions and reduce cardiovascular events, these agents have the effect of increasing fluid retention in patients, which results in more hospitalizations for congestive heart failure. The PPAR α / γ dual agonists are developed to increase insulin sensitivity and simultaneously prevent diabetic cardiovascular complications. Such compounds are under clinical trials and proposed for treatment of type II diabetes with secondary cardiovascular complications. However, PPAR α / γ dual agonists such as muraglitazar, tesaglitazar and ragaglitazar have been noted to produce several cardiovascular risks and carcinogenicity, which raised number of questions about the clinical applications of dual agonists in diabetes and its associated complications. Therefore future studies of PPAR-γ agonists or dual PPAR-α/γ agonists will require further delineation of the risk profile to avoid adverse outcomes in susceptible patients. Key Words Peroxisome proliferated-activated receptors, Type II diabetes, Dual agonist.

Introduction Identification of molecular atherosclerosis and diabetes. mechanisms of the transducer proteins Cardiovascular disorders are the most involved in metabolic and anabolic common cause of morbidity and pathways is crucial for understanding mortality in diabetes and their the energy homeostasis in the human prevalence is increasing constantly in body and to develop new therapeutic developing countries. Diabetes is a agents for the treatment of chronic metabolic disorder characterized by metabolic disorders such as, insulin resistance and reduced secretion of insulin and is associated *Corresponding Author: with cardiovascular pathologies such [email protected] as atherosclerosis, hypertension,

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Kishan Patel et al., Current Pharma Research., Vol. 3(2), 2013, 846-854. endothelial dysfunction, cardiac PPARs (PPARα, PPARγ, PPARβ/δ) dysfunction and myocardial are transcription factors that regulate infarction. The peroxisome gene transcription by binding to proliferator-activated receptors specific DNA response elements upon (PPARs) are a group of nuclear ligand activation and receptor proteins that function as heterodimerization with the 9-cis transcription factors regulating the retinoic acid receptor. Ligand-induced expression of genes1. PPARs play conformational changes induce the essential roles in the regulation of recruitment of coactivators that cellular differentiation, development, transmit transcription activation and metabolism (carbohydrate, lipid, signals to basal transcriptional protein), and tumorigenesis2 of higher machinery6. Depending upon the organisms3, 4. activating ligand, different receptor Types of PPAR conformations are adopted, leading to To date, three major types of PPAR, differential coactivator recruitment encoded by separate genes, have been and subsequent downstream effects on identified; they are PPAR- α gene expression (Figure 2). Selective (NR1C1), PPAR- δ/ β (NR1C2) and modulation has been described both PPAR-γ (NR1C3). Functions of for PPARα (selective peroxisome PPARs and conditions that are the proliferator-activated receptor α targets of PPAR agonists are modulator [SPPARαM])7 and PPARγ summarized in Table 1. [SPPARγM]8, and could explain the Like other nuclear receptors, PPARs differences seen in biological activity are modular in structure and contain of ligands, even those belonging to the the following functional domains: same pharmacological class. Thus, the (A/B) N-terminal region selective modulator concept provides (C) DBD (DNA-binding a molecular approach to develop domain) ligands devoid of adverse effects, (D) flexible hinge region while maintaining the desirable 9 (E) LBD ( ligand binding biological efficacy . The gene domain) transcription mechanism is identical in (F) C-terminal region all PPAR subtypes. Important The DBD contains two zinc finger biological effects of each individual motifs, which bind to specific PPAR isoform are shown in Figure 3. sequences of DNA known as hormone PPAR Ligands: response elements when the receptor Chemical structures of some PPAR is activated. The LBD has an ligands are given below (Figure 4): extensive secondary structure PPARα AND PPARγ AS A DUAL consisting of 13 alpha helices and a AGONIST: beta sheet5. Natural and synthetic PPARα/γ dual agonists are new class ligands bind to the LBD, either of drugs, which have been developed activating or repressing the receptor. to target both PPARα and PPARγ simultaneously in order to produce synergistic anti diabetic and cardio

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Kishan Patel et al., Current Pharma Research., Vol. 3(2), 2013, 846-854. protective effects. Simultaneous muraglitazar has efficiently reduced activation of PPARα and γ activators hemoglobin A1C and improved the might, through a complementary lipid profile in diabetic patients13. mechanism of action, alter the tissue However, the clinical study with distribution of fatty acids by muraglitazar was discontinued stimulating their uptake and utilization recently due to higher incidence of in adipose tissue, liver and skeletal edema and heart failure17. Tesaglitazar muscle (Figure 5). The recently has been shown to reduce investigated PPARα/γ dual agonists atherosclerosis in the LDL receptor are naveglitazar, netoglitazone, deficient mice probably by its direct muraglitazar, ragaglitazar, actions on the vessels18. Further, tesaglitazar, imiglitazar, MK 767, LY tesaglitazar has been suggested to 929 and LSN86210. The PPARα/γ have beneficial effects on both dual agonists are noted to reduce hyperglycemia and dyslipidemia19. triglycerides, raise cardioprotective However its development has been HDL levels and consequently improve terminated due to the elevated serum insulin sensitivity6,11–13. Treatment creatinine and associated decreases in with ragaglitazar significantly reduced glomerular filtration rate20. These blood pressure in spontaneously discouraging results with muraglitazar hypertensive rats and improved and tesaglitazar have raised a number endothelial function in Zucker of questions about the role of diabetic fatty (ZDF) rats when PPARα/γ dual agonists in diabetic compared with pioglitazone complications. The balanced binding treatment14. Moreover, it has been affinity of PPARα/γ dual agonists reported that treatment with DRF towards both the receptor subtypes is 2519, a PPAR α/γ dual agonist has necessary to give optimal biological resulted in better lipid profile and effects of both PPARα-mediated and enhanced aortic smooth muscle PPARγ-mediated actions. Supra relaxation in ZDF rats when compared therapeutic activation of PPARα or with rosiglitazone treatment15. These PPARγ may be associated with results exemplify the beneficial effects adverse effects such as of dual PPAR α/γ dual agonist in carcinogenesis, renal dysfunction, improving the cardiovascular risk fluid retention and heart failure21–23. factors. The PPARγ agonists are The muraglitazar has high affinity shown to increase adipogenesis and towards PPARγ and tesaglitazar body weight, whereas PPARα possesses more affinity towards agonists counteract these effects by PPARα20. Thus, the lack of balance in decreasing food intake and fat binding affinity may lead to supra- deposits in animals11, 16. Thus, therapeutic expression of the stronger increase in body weight observed with agonist which may cause adverse PPARγ treatment may not be effects. The clinical study in which associated with PPARα/γ dual dual PPARα/γ stimulation by means agonists. However, such effects are of concomitant administration of not clear in human situation. The fenofibrate and rosiglitazone

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Kishan Patel et al., Current Pharma Research., Vol. 3(2), 2013, 846-854. improved atherogenic dyslipidemic under development to prevent the profile in patients with good diabetic cardiovascular complications. tolerability24. Hence, the future development of dual agonists with References selective and balanced PPARα/γ 1. Michalik L, Auwerx J, Berger activity may be appropriate and JP, Chatterjee VK, Glass CK, sensible option. One of the challenges Gonzalez FJ, Grimaldi PA, of the development of PPAR dual Kadowaki T, Lazar MA, agonists is that one single molecule O'Rahilly S, Palmer CN, has to cause the appropriate Plutzky J, Reddy JK, pharmacological profile by interaction Spiegelman BM, Staels B, with two or more different receptors Wahli W: "International Union that are expressed in two or more of Pharmacology. LXI. different sites of action. Peroxisome proliferator- activated receptors". Conclusion Pharmacol. Rev. 2006, 58 (4): Cardiovascular complications are 726–41. known to alter the life style and 2. Belfiore A, Genua M, reduce the life time of patients with Malaguarnera R: "PPAR- diabetes. PPAR agonists have gamma Agonists and Their emerged as a promising group of Effects on IGF-I Receptor agents for treating Type II diabetes Signaling: Implications for and associated cardiovascular risk Cancer". PPAR Res 2009: factors. The dual agonists have been 830501. proposed to reduce hyperglycemia, 3. Berger J, Moller DE: "The hyperlipidemia and simultaneously mechanisms of action of prevent the progression of PPARs". Annu. Rev. Med. cardiovascular complications. 2002, 53: 409–35. Unfortunately, the clinical 4. Feige JN, Gelman L, Michalik development of few PPARα/γ dual L, Desvergne B, Wahli W: agonists such as muraglitazar and "From molecular action to tesaglitazar etc. has been discontinued physiological outputs: due to their undesirable peroxisome proliferator- pharmacological effects. The side activated receptors are nuclear effects of these agents may be due to receptors at the crossroads of their imbalanced and supra- key cellular functions". Prog. therapeutic activity on PPARγ and Lipid Res. 2006, 45 (2): 120– PPARα. Therefore, the dual agonists 59. with selective and balanced agonistic 5. Zoete V, Grosdidier A, activity on PPARα/γ could be an Michielin O:"Peroxisome appropriate therapeutic option. The proliferator-activated receptor PPARα/δ dual agonists and structures: ligand specificity, PPARα/γ/δ pan agonists are currently molecular switch and interactions with regulators".

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Biochim. Biophys. Acta. 2007, PPAR agonists: multimodal 1771 (8): 915–25. drugs for the treatment of type 6. Fievet C, Fruchart JC, Staels 2 diabetes and atherosclerosis. B: PPARα and PPARγ dual Expert Opin Emerg Drugs agonists for the treatment of 2006, 11:379–401. type 2 diabetes and the 11. Etgen GJ, Oldham BA, metabolic syndrome. Current Johnson WT, Broderick CL, Opinion in Pharmacology Montrose CR, Brozinick JT: 2006, 6:606-614. The dual peroxisome 7. Duez H, Lefebvre B, Poulain proliferator–activated P, Torra IP, Percevault F, Luc receptor–α/γ agonist G, Peters JM, Gonzalez FJ, LY465608 ameliorates insulin Gineste R, Helleboid S et al.: resistance and diabetic Regulation of human apoA-I hyperglycemia while by gemfibrozil and fenofibrate improving cardiovascular risk through selective peroxisome factors in preclinical models. proliferator-activated receptor Diabetes 2002, 51:1083–7. alpha modulation. Arterioscler 12. Humphries PS, Almaden JV, Thromb Vasc Biol 2005, Barnum SJ, Carlson TJ, Do 25:585-591. QQT, Fraser JD: Pyridine-2- 8. Camp HS, Li O, Wise SC, propanoic acids: discovery of Hong YH, Frankowski CL, dual PPARα/γ agonists as Shen X, Vanbogelen R, Leff antidiabetic agents. Bioorg T: Differential activation of Med Chem Lett 2006, peroxisome proliferator- 16:6116–9. activated receptor-gamma by 13. Kendall MD, Rubin CJ, troglitazone and rosiglitazone. Mohideen P, Ledeine JM, Diabetes 2000, 49:539-547. Belder R, Gross J: 9. Burgermeister E, Schnoebelen Improvement of glycemic A, Flament A, Benz J, Stihle control, triglycerides, and M, Gsell B, Rufer A, Ruf A, HDL cholesterol levels with Kuhn B, Marki HP et al.: A muraglitazar, a dual novel partial agonist of (alpha/gamma) peroxisome peroxisome proliferator- proliferatoractivated receptor activated receptor-gamma activator, in patients with type (PPARgamma) recruits 2 diabetes inadequately PPARgamma-coactivator- controlled with metformin 1alpha, prevents triglyceride monotherapy: a double-blind, accumulation, and potentiates randomized, pioglitazone- insulin signaling in vitro. Mol comparative study. Diabetes Endocrinol 2006, 20:809-830. Care 2006, 29:1016–23. 10. Pourcet B, Fruchart JC, Staels 14. Mamnoor PK, Hegde P, Datla B, Glineur C: Selective PPAR SR, Damarla RK, Rajagopalan modulators, dual and pan R, Chakrabarti R:

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Fig. 1: Schematic representation of the functional domains of PPARs.

PPAR RXR

Ligand 1 PPAR AGGTCANAGGTCA PPRE

Common Specific 1 2 co-factors co-factors

Shared biological action PPRE Distinct biological action Ligand 2 PPAR AGGTCANAGGTCA

PPAR RXR

Fig. 2: Ligands interact with the PPAR receptor to induce ligand-specific conformational changes.

PPARγ PPARα PPARβ

Cellular Actions Skeletal Muscle Liver Vessel Wall Heart Skeletal Muscle/Liver/Adipocyte

↓ Cytokines ↑ Glucose ↑ FA ↓ Cytokines ↓ FA ↑ FA Uptake oxidation oxidation oxidation ↓ Resistin ↑ ABCA1 ↑ Glycogen ↑ ApoA-1 ↓ LPL ↑ UCP ↓ FFA synthesis ↓ NF-ĸB ↓ ApoC-III ↓ TG ↑ ABCA1 ↑ ApoE ↑ LPL ↑ LDL ↓ NF-ĸB

↑ GLUT4

Insulin sensitivity Blood Lipid homeostasis Glucose homeostasis ↓ TG ↓ FFA Glucose homeostasis Vascular integrity ↑ HDL ↓ VLDL Vascular integrity

Fig. 3: PPARs gene transcription mechanisms and their biologic effects in different organs.

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Fig. 4: Chemical structures of PPAR ligands.

PPARα Balanced Dual Agonist PPARγ

Liver Skeletal Muscle Heart Blood Vessels

↓ TG Synthesis ↑ Triacylglycerol ↓ Signalling Proteins ↓ Adhesion molecules combustion ↓ Apo C III ↓ Transcription ↑ ABCA 1 ↑ Insulin sensitive factors ↑ HDL glucose uptake ↑ Cholesterol efflux ↓ Cardiac lipid from macrophages ↑ β oxidation ↑ GLUT-4 synthesis accumulation ↓ Proinflammatory ↑ Apo A I,II gene expression

↓ Steatohepatitis ↑ Insuline sensitivity ↓ Atherosclerosis ↑ Endothelial function ↓ Hyperglycemia ↓ Hyperlipidemia ↓ Oxidative stress ↑ Cardiac function

Fig. 5: The synergistic beneficial actions of balanced PPARα/γ dual agonists.

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Table 1: Human PPARs as Targets in the Metabolic Syndrome.

Receptor Functions Conditions targeted by Agonists PPARα Controls lipid metabolism. Atherogenic dyslipidemia (elevated serum triglycerides and low HDL). Target of fibrate drugs. PPARγ Controls glucose metabolism Insulin resistance in type 2 and adipocyte differentiation. diabetes. Target of thiazolidinediones. PPARδ Appears to control multiple Metabolic syndrome, obesity, aspects of the metabolic atherosclerosis. syndrome.

Table 2: Current Status of Preclinical and Clinical Progress of PPAR Dual and Pan Agonists25

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