Best Practice & Research Clinical Endocrinology & Metabolism
Volume 21, Issue 4 , Pages 687-710 , December 2007

PPAR agonists: multimodal drugs for the treatment of type-2 diabetes

  • Bart Staels, PhD (Professor and Head of Laboratory)

      Affiliations

    • Corresponding Author InformationCorresponding author. Tel.: +33 3 20 87 73 88; Fax: +33 3 20 87 71 98.

References 

  1. Pascual G, Fong AL, Ogawa S, et al. A SUMOylation-dependent pathway mediates transrepression of inflammatory response genes by PPAR-gamma. Nature. 2005;437:759–763
  2. Staels B, Dallongeville J, Auwerx J, et al. Mechanism of action of fibrates on lipid and lipoprotein metabolism. Circulation. 1998;98:2088–2093
  3. Chinetti G, Lestavel S, Bocher V, et al. PPARα and PPARγ activators induce cholesterol removal from macrophage foam cells through stimulation of the ABCA1 pathway. Nature Medicine. 2001;7:53–58
  4. Barbier O, Pineda Torra I, Duguay Y, et al. Pleotropic actions of peroxisome proliferator-activated receptors in lipid metabolism and atherosclerosis. Arteriosclerosis Thrombosis and Vascular Biology. 2002;22:717–726
  5. Staels B, Fruchart J. Therapeutic roles of peroxisome proliferator-activated receptor agonists. Diabetes. 2005;54:2460–2470
  6. Rubins HB, Robins SJ, Collins D, et al. Gemfibrozil for the secondary prevention of coronary heart disease in men with low levels of high-density lipoprotein cholesterol. Veterans Affairs High-Density Lipoprotein Cholesterol Intervention Trial Study Group. The New England Journal of Medicine. 1999;341:410–418
  7. Frick MH, Elo O, Haapa K, et al. Helsinki Heart Study: primary-prevention trial with gemfibrozil in middle-aged men with dyslipidemia. Safety of treatment, changes in risk factors, and incidence of coronary heart disease. The New England Journal of Medicine. 1987;317:1237–1245
  8. DAIS-Group . Effect of fenofibrate on progression of coronary-artery disease in type-2 diabetes: the diabetes atherosclerosis intervention study, a randomised study. Lancet. 2001;357:905–910
  9. Keech A, Simes RJ, Barter P, et al. Effects of long-term fenofibrate therapy on cardiovascular events in 9795 people with type-2 diabetes mellitus (the FIELD study): randomised controlled trial. Lancet. 2005;366:1849–1861
  10. Kersten S, Seydoux J, Peters JM, et al. Peroxisome proliferator-activated receptor α mediates the adaptive response to fasting. The Journal of Clinical Investigation. 1999;103:1489–1498
  11. Wu P, Peters JM, Harris RA. Adaptive increase in pyruvate kinase 4 during starvation is mediated by peroxisome proliferator-activated receptor α. Biochemical and Biophysical Research Communications. 2001;287:391–396
  12. Xu J, Xiao G, Trujilo C, et al. Peroxisome proliferator-activated receptor α (PPARα) influences substrate utilization for hepatic glucose production. The Journal of Biological Chemistry. 2002;277:50237–50244
  13. Guerre-Millo M, Rouault C, Poulain P, et al. PPAR-α-null mice are protected from high-fat diet-induced insulin resistance. Diabetes. 2001;50:2809–2814
  14. Guerre-Millo M, Gervois P, Raspé E, et al. PPARα activators improve insulin sensitivity and reduce adiposity. The Journal of Biological Chemistry. 2000;275:16638–16642
  15. Lalloyer F, Vandewalle B, Percevault F, et al. Peroxisome proliferator-activated receptor α improves pancreatic adaptation to insulin resistance in obese mice and reduces lipotoxicity in human islets. Diabetes. 2006;55:1605–1613
  16. Ravnskjaer K, Boergesen M, Rubi B, et al. Peroxisome proliferator-activated receptor α (PPARα) potentiates, whereas PPARγ attenuates, glucose-stimulated insulin secretion in pancreatic β-cells. Endocrinology. 2005;146:3266–3276
  17. Steiner G. Altering TG concentrations changes insulin-glucose relationships in hypertriglyceridemic patients. Double-blind study with gemfibrozil with implications for atherosclerosis. Diabetes Care. 1991;14:1077–1081
  18. Ferrari C, Romussi M, Bertazzoni A, et al. Effects of short-term clofibrate administration on glucose tolerance and insulin secretion in patients with chemical diabetes or hypertriglyceridemia. Metabolism. 1977;26:129–139
  19. Murakami K, Nambu S, Koh H, et al. Clofibrate enhances the affinity of insulin receptors in non-insulin dependent diabetes mellitus. British Journal of Clinical Pharmacology. 1984;17:89–91
  20. Kobayashi M, Shigeta Y, Hirata Y, et al. Improvement of glucose tolerance in NIDDM by clofibrate. Randomized double-blind study. Diabetes Care. 1988;11:495–499
  21. Flavell DM, Ireland H, Stephens JW, et al. Peroxisome proliferator-activated receptor alpha gene variation influences age of onset and progression of type 2 diabetes. Diabetes. 2005;54:582–586
  22. Andrulionyte L, KIuulasmaa T, Chiasson JL, et al. Single nucleotide polymorphisms of the peroxisome proliferator-activated receptor-α gene (PPARA) influence the conversion from impaired glucose tolerance to type 2 diabetes. Diabetes. 2007;56:1181–1186
  23. Rubenstrunk A, Hanf R, Hum DW, et al. Safety issues and prospects for future generations of PPAR modulators. Biochimica et Biophysica Acta. 2007;1771:1065–1081
  24. Buchanan TA, Xiang AH, Peters RK, et al. Preservation of pancreatic beta-cell function and prevention of type-2 diabetes by pharmacological treatment of insulin resistance in high-risk Hispanic women. Diabetes. 2002;51:2796–2803
  25. Xiang AH, Peters RK, Kjos SL, et al. Effect of pioglitazone on pancreatic beta-cell function and diabetes risk in Hispanic women with prior gestational diabetes. Diabetes. 2006;55:517–522
  26. The DREAM Trial Investigators . Effect of rosiglitazone on the frequency of diabetes in patients with impaired glucose tolerance or impaired fasting glucose: a randomised controlled trial. The Lancet. 2006;368:1096–1105
  27. Chiasson JL, Josse RG, Gomis R, et al. Acarbose for prevention of type-2 diabetes mellitus: the STOP-NIDDM randomised trial. The Lancet. 2002;359:2072–2077
  28. Knowler WC, Barrett-Connor E. Reduction in the incidence of type-2 diabetes with lifestyle intervention or metformin. The New England Journal of Medicine. 2002;346:393–403
  29. Kahn SE, Haffner SM, Heise MA, et al. Glycemic durability of rosiglitazone, Metformin, or Glyruride monotherapy. The New England Journal of Medicine. 2006;355:2427–2443
  30. Arner P. The adipocyte in insulin resistance: key molecules and the impact of the thiazolidinediones. Trends in Endocrinology and Metabolism. 2003;14:137–145
  31. Kahn CR, Chen L, Cohen SE. Unraveling the mechanism of thiazolidinediones. The Journal of Clinical Investigation. 2000;106:1305–1307
  32. Kramer D, Shapiro R, Adler A, et al. Insulin-sensitizing effect of rosiglitazone (BRL-49653) by regulation of glucose transporters in muscle and fat of Zucker rats. Metabolism. 2001;50:1294–1300
  33. Baumann C, Chokshi N, Saltiel A, et al. Cloning and characterization of a functional peroxisome proliferator activated receptor-γ-responsive element in the promoter of the CAP gene. The Journal of Biological Chemistry. 2000;275:9131–9135
  34. Yamauchi T, Kamon J, Waki H, et al. The fat-derived hormone adiponectin reverses insulin resistance associated with both lipoatrophy and obesity. Nature Medicine. 2001;7:941–946
  35. Hevener AL, Olefsky JM, Reichart D, et al. Macrophage PPAR gamma is required for normal skeletal muscle and hepatic insulin sensitivity and full antidiabetic effects of thiazolidinediones. The Journal of Clinical Investigation. 2007;117:1658–1669
  36. Odegaard JI, Ricardo-Gonzalez RR, Goforth MH, et al. Macrophage-specific PPARgamma controls alternative activation and improves insulin resistance. Nature. 2007;447:1116–1120
  37. Higa M, Zhou Y, Ravazzola M, et al. Troglitazone prevents mitochondrial alterations, β-cell destruction, and diabetes in obese prediabetic rats. Proceedings of the National Academy of Sciences of the United States of America. 1999;96:11513–11518
  38. Kim HI, Ahn YH. Role of peroxisome proliferator-activated receptor-gamma in the glucose-sensing apparatus of liver and beta-cells. Diabetes. 2004;53(Suppl 1):S60–S65
  39. Díaz-Delfín J, Morales M, Caelles C. Hypoglycemic action of thiazolidinediones/peroxisome proliferator-activated receptor {gamma} by inhibition of the c-Jun N-terminal kinase pathway. Diabetes. 2007;56:1865–1871
  40. Ishida H, Takizawa M, Ozawa S, et al. Pioglitazone improves insulin secretory capacity and prevents the loss of beta-cell mass in obese diabetic db/db mice: Possible protection of beta cells from oxidative stress. Metabolism. 2004;53:488–494
  41. Elte JWF, Blicklé JF. Thiazolidinediones for the treatment of type 2 diabetes. European Journal of Internal Medicine. 2007;18:18–25
  42. Li AC, Brown KK, Silvestre MJ, et al. Peroxisome proliferator-activated receptor γ ligands inhibits development of atherosclerosis in LDL receptor-deficient mice. The Journal of Clinical Investigation. 2000;106:523–531
  43. Akiyama TE, Sakai S, Lambert G, et al. Conditional disruption of the peroxisome proliferator-activated receptor γ gene in mice results in lowered expression of ABCA1, ABCG1, and apoE in macrophages and reduced cholesterol efflux. Molecular and Cellular Biology. 2002;22:2607–2619
  44. Chinetti G, Gbaguidi FG, Griglio S, et al. CLA-1/SR-BI is expressed in atherosclerotic lesion macrophages and regulated by activators of peroxisome prolifertor-activated receptors. Circulation. 2000;101:2411–2417
  45. Dormandy JA, Charbonnel B, Eckland DJ, et al. Secondary prevention of macrovascular events in patients with type-2 diabetes in the PROactive Study (PROspective pioglitAzone Clinical Trial in macroVascular Events): a randomized controlled trial. Lancet. 2005;366:1279–1289
  46. Sznaidman ML, Haffner CDH, Maloney PR, et al. Novel selective small molecule agonists for peroxisome proliferator-activated receptor δ (PPARδ)-synthesis and biological activity. Bioorganic & Medicinal Chemistry Letters. 2003;11:1517–1521
  47. Basséne CE, Suzenet F, Hennuyer N, et al. Studies towards the conception of new selective PPARbeta/delta ligands. Bioorganic & Medicinal Chemistry Letters. 2006;16:4528–4532
  48. Pereira R, Gaudon C, Iglesias B, et al. Synthesis of the PPARβ/δ-selective agonist GW501516 and C4-thiazole-substituted analogs. Bioorganic & Medicinal Chemistry Letters. 2006;16:49–54
  49. Kasuga J, Nakagome I, Aoyama A, et al. Design, synthesis, and evaluation of potent, structurally novel peroxisome proliferator-activated receptor (PPAR) delta-selective agonists. Bioorganic & Medicinal Chemistry. 2007;15:5177–5190
  50. Oliver WR, Shenk JL, Snaith MR, et al. A selective peroxisome proliferator-activated receptor δ agonist promotes reverse cholesterol transport. Proceedings of the National Academy of Sciences of the United States of America. 2001;98:5306–5311
  51. van der Veen JN, Kruit JK, Havinga R, et al. Reduced cholesterol absorption upon PPARδ activation coincides with decreased intestinal expression of NPC1L1. Journal of Lipid Research. 2005;46:526–534
  52. Wallace JM, Schwartz M, Cowaord P, et al. Effects of peroxisome-activated receptor α/δ agonists on HDL-cholesterol in vervet monkeys. Journal of Lipid Research. 2005;46:1009–1016
  53. Dressel U, Allen TL, Pippal JB, et al. The peroxisome proliferator-activated receptor β/δ agonist, GW501516, regulates the expression of genes involved in lipid catabolism and energy uncoupling in skeletal muscle cells. Molecular Endocrinology. 2003;17:2477–2493
  54. Sprecher DL, Massien C, Pearce G, et al. Triglyceride: High-density lipoprotein cholesterol effects in healthy subjects administered a peroxisome proliferator activated receptor δ agonist. Arteriosclerosis Thrombosis and Vascular Biology. 2006;27:359–365
  55. Rival Y, Benéteau N, Taillandier T, et al. PPARα and PPARδ activators inhibit cytokine-induced nuclear translocation of NF-κB and expression of VCAM-1 in EAhy926 endothelial cells. European Journal of Pharmacology. 2002;435:143–151
  56. Lee C-H, Chawla A, Urbiztondo N, et al. Transcriptional repression of atherogenic inflammation: modulation by PPARδ. Science. 2003;302:453–457
  57. Li AC, Binder CJ, Gutierrez A, et al. Differential inhibition of macrophage foam-cell formation and atherosclerosis in mice by PPARα, β/δ, and γ. The Journal of Clinical Investigation. 2004;114:1564–1576
  58. Welch JS, Ricote M, Akiyama TE, et al. PPARγ and PPARδ negatively regulate specific subsets of lipopolysaccharide and IFN-γ target genes in macrophages. Proceedings of the National Academy of Sciences of the United States of America. 2003;100:6712–6717
  59. Zhang J, Fu M, Zhu X, et al. Peroxisome proliferator-activated receptor delta is up-regulated during vascular lesion formation and promotes post-confluent cell proliferation in vascular smooth muscle cells. The Journal of Biological Chemistry. 2002;29:11505–11512
  60. Graham TL, Mookherjee C, Suckling KE, et al. The PPARδ agonist GW0742X reduces atherosclerosis in LDLR–/– mice. Atherosclerosis. 2005;181:29–37
  61. Tanaka T, Yamamoto J, Iwasaki S, et al. Activation of peroxisome proliferator-activated receptor δ induces fatty acid oxidation in skeletal muscle and attenuates metabolic syndrome. Proceedings of the National Academy of Sciences of the United States of America. 2003;100:15924–15929
  62. Wang Y-X, Lee C-H, Tiep S, et al. Peroxisome proliferator-activated receptor δ activates fat metabolism to prevent obesity. Cell. 2003;113:159–170
  63. Luquet S, Lopez-Soriano J, Holst D, et al. Peroxisome proliferator-activated receptor δ controls muscle development and oxidative capability. The FASEB Journal. 2003;17:2299–2301
  64. Wang Y-X, Zhang C-L, Yu RT, et al. Regulation of muscle fiber type and running endurance by PPARδ. PLoS Biology. 2004;2:e294
  65. Choi KC, Lee SY, Yoo HJ, et al. Effect of PPAR-delta agonist on the expression of visfatin, adiponectin, and resistin in rat adipose tissue and 3T3-L1 adipocytes. Biochemical and Biophysical Research Communications. 2007;357:62–67
  66. Krämer DK, Al-Kahlili L, Perrini S, et al. Direct activation of glucose transport in primary human myotubes after activation of peroxisome proliferator-activated receptor δ. Diabetes. 2005;54:1157–1163
  67. Krämer DK, Al-Kahlili L, Guigas B, et al. Role of AMP kinase and PPARδ in the regulation of lipid and glucose metabolism in human skeletal muscles. The Journal of Biological Chemistry. 2007;282:19313–19320
  68. Lee CH, Olson P, Hevener A, et al. PPARδ regulates glucose metabolism and insulin sensitivity. Proceedings of the National Academy of Sciences of the United States of America. 2006;103:3444–3449
  69. Pelton P. GW-501516 GlaxoSmithKline/Ligand. Current Opinion in Investigational Drugs. 2006;7:360–370
  70. Leibowitz MD, Fievet C, Hennuyer N, et al. Activation of PPARδ alter lipid metabolism in db/db mice. FEBS letters. 2000;473:333–336
  71. Sprecher DL, Johnson A, Pearce G, et al. Effects of a peroxisome proliferator-activated receptor (PPAR) δ agonist on apolipoprotein B-100 kinetics in the metabolic syndrome. Circulation. 2005;112:Suppl Abs 1211
  72. Gupta RA, Wang D, Katkuri S, et al. Activation of nuclear hormone receptor peroxisome proliferator-activated receptor-delta accelerates intestinal adenoma growth. Nature Medicine. 2004;10:245–247
  73. Piqueras L, Reynolds AR, Hodivala-Dilke KM, et al. Activation of PPARbeta/delta induces endothelial cell proliferation and angiogenesis. Arteriosclerosis Thrombosis and Vascular Biology. 2007;27:63–69
  74. Rocchi S, Picard F, Vamecq J, et al. A unique PPARgamma ligand with potent insulin-sensitizing yet weak adipogenic activity. Molecular Cell. 2001;8:737–747
  75. Berger J, Petro AE, Macnaul KL, et al. Distinct properties and advantages of a novel peroxisome proliferator-activated protein [gamma] selective modulator. Molecular Endocrinology. 2003;17:662–676
  76. Pourcet B, Fruchart J, Staels B, et al. Selective PPAR modulators, dual and pan PPAR agonists: multimodal drugs for the treatment of type-2 diabetes and atherosclerosis. Expert Opinion on Emerging Drugs. 2006;11:379–401
  77. Zhang F, Lavan BE, Gregoire FM. Selective modulators of PPAR-γ activity: molecular aspects related to obesity and side-effects. PPAR Research. 2007;2007:32696
  78. Gelman L, Feige JN, Desvergne B. Molecular basis of selective PPARγ modulation for the treatment of type 2 diabetes. Biochimica et Biophysica Acta. 2007;1771:1094–1107
  79. Zhang F, Clemens EL, Gregoire FM, et al. Metaglidasen, a novel selective peroxisome proliferative-activated receptor-γ modulator, preserves pancreatic islet structure and function in db/db mice. Diabetes. 2006;55:1396
  80. Rosenstock J, Flores-Loranzo F, Schwartz S, et al. MBX-102: a novel non-TZD insulin sensitizer that improves glycemic control without causing edema or weight gain in patients with type-2 diabetes (T2DM) on concomitant insulin therapy. Diabetes. 2005;54:A11
  81. Schupp M, Clemenz M, Gineste R, et al. Molecular characterization of new selective peroxisome proliferator-activated receptor gamma modulators with angiotensin receptor blocking activity. Diabetes. 2005;54:3442–3452
  82. Duez H, Lefebvre B, Poulain P, et al. Regulation of human apoA-I by gemfibrozil and fenofibrate through selective peroxisome proliferator-activated receptor alpha modulation. Arteriosclerosis Thrombosis and Vascular Biology. 2005;25:585–591
  83. Boden G, Homko C, Mozzoli M, et al. Combined use of rosiglitazone and fenofibrate in patients with type 2 diabetes: prevention of fluid retention. Diabetes. 2007;56:248–255
  84. Oakes ND, Thalén P, Hultstrand T, et al. Tesaglitazar, a dual PPAR{alpha}/{gamma} agonist, ameliorates glucose and lipid intolerance in obese Zucker rats. American Journal of Physiology. Regulatory, Integrative and Comparative Physiology. 2005;289:R938–R946
  85. Chakrabarti R, Vikramadithyan RK, Misra P, et al. Ragaglitazar: a novel PPAR alpha PPAR gamma agonist with potent lipid-lowering and insulin-sensitizing efficacy in animal models. British Journal of Pharmacology. 2003;140:527–537
  86. Bergeron R, Yao J, Woods JW, et al. Peroxisome proliferator-activated receptor (PPAR)-alpha agonism prevents the onset of type-2 diabetes in Zucker diabetic fatty rats: A comparison with PPAR gamma agonism. Endocrinology. 2006;147:4252–4262
  87. Tozzo E, Ponticiello R, Swartz J, et al. The dual peroxisome proliferator-activated receptor alpha/gamma activator muraglitazar prevents the natural progression of diabetes in db/db mice. The Journal of Pharmacology and Experimental Therapeutics. 2007;321:107–115
  88. Zadelaar AS, Boesten LS, Jukema JW, et al. Dual PPARalpha/gamma agonist tesaglitazar reduces atherosclerosis in insulin-resistant and hypercholesterolemic ApoE*3Leiden mice. Arteriosclerosis Thrombosis and Vascular Biology. 2006;26:2560–2566
  89. Chira EC, McMillen TS, Wang S, et al. Tesaglitazar, a dual peroxisome proliferator-activated receptor alpha/gamma agonist, reduces atherosclerosis in female low density lipoprotein receptor deficient mice. Atherosclerosis. 2007;195:100–109
  90. Buse JB, Rubin CJ, Fredenrich R, et al. Muraglitazar, a dual (α/γ) PPAR activator: a randomized, double-blind, placebo-controlled, 24-week monotherapy trial in adult patienst with type2 diabetes. Clinical Therapeutics. 2005;27:1181–1195
  91. Nissen SE, Wolski K, Topol EJ. Effect of muraglitazar on death and major adverse cardiovascular events in patients with type-2 diabetes mellitus. JAMA : the Journal of the American Medical Association. 2005;294:2581–2586
  92. Kendall DM, Rubin CJ, Mohideen P, et al. Improvement of glycemic control, triglycerides, and HDL cholesterol levels with muraglitazar, a dual (alpha/gamma) peroxisome proliferator-activated receptor activator, in patients with type-2 diabetes inadequately controlled with metformin monotherapy: A double-blind, randomized, pioglitazone-comparative study. Diabetes Care. 2006;29:1016–1023
  93. Goldstein BJ, Rosenstock J, Anzalone D, et al. Annual Meeting of American Diabetes Association, San Diego, June 2005, abstract 83-OR.
  94. Schuster HM, Fagerberg B, Edwards S, et al. Annual Meeting of American Diabetes Association, San Diego, June 2005 abstract 615-P.
  95. Saad MF, Greco S, Osei K, et al. Ragaglitazar improves glycemic control and lipid profile in type 2 diabetic subjects: a 12-week, double-blind, placebo-controlled dose-ranging study with an open pioglitazone arm. Diabetes Care. 2004;27:1324–1329
  96. Prince M, Spicer K, Caro J, et al. Efficacy of LY519818, a novel non-TZD, PPAR-γ dominant αγ dual agonist. Diabetes. 2004;52(Suppl 2):A33
  97. Fiévet C, Fruchart JC, Staels B. PPARα and PPARγ dual agonists for the treatment of type-2 diabetes and the metabolic syndrome. Current Opinion in Pharmacology. 2006;6:606–614
  98. Liu KG, Lambert MH, Leesnitzer LW, et al. Identification of a serie of PPARγ/δ dual agonists via solid-phase parallel synthesis. Bioorganic & Medicinal Chemistry Letters. 2001;11:2959–2962
  99. Gonzalez IC, Lamar J, Iradier F, et al. Design and synthesis of a novel class of dual PPARγ/δ agonists. Bioorganic & Medicinal Chemistry Letters. 2007;17:1052–1055
  100. Xu Y, Etgen GJ, Broderick CL, et al. Design and synthesis of dual peroxisome proliferator-activated receptors γ and δ agonists as novel euglycemic agents with a reduced weight gain profile. Journal of Medicinal Chemistry. 2006;49:5649–5652
  101. Kasuga J, Yamasaki D, Raraya Y, et al. Design, synthesis, and evaluation of a novel series of alpha-substituted phenylpropanoic acid derivatives as human peroxisome proliferator-activated receptor (PPAR) alpha/delta dual agonists for the treatment of metabolic syndrome. Bioorganic & Medicinal Chemistry. 2006;14:8405–8414
  102. Tenenbaum A, Motro M, Fisman E. Dual and pan-peroxisome proliferator-activated receptors (PPAR) co-agonism: the bezafibrate lessons. Cardiovascular Diabetology. 2005;4:14
  103. Elkeles RS, Diamond JR, Poulter C, et al. Cardiovascular outcomes in type 2 diabetes. A double-blind placebo-controlled study of bezafibrate: the St. Mary's, Ealing, Northwick Park Diabetes Cardiovascular Disease Prevention (SENDCAP) Study. Diabetes Care. 1998;21:641–648
  104. The BIP Study Group . Secondary prevention by raising HDL cholesterol and reducing triglycerides in patients with coronary disease: the Bezafibrate Infarction Prevention (BIP) study. Circulation. 2000;102:21–27
  105. Etgen GJ, Oldham BA, Johnson WT, et al. A tailored therapy for the metabolic syndrome: the dual peroxisome proliferator-activated receptor-alpha/gamma agonist LY465608 ameliorates insulin resistance and diabetic hyperglycemia while improving cardiovascular risk factors in preclinical models. Diabetes. 2002;51:1083–1087
  106. Mohindroo N, Hunag CF, Peng YH, et al. Novel indole-based peroxisome proliferator-activated receptor agonists: design, SAR, structural biology, and biological activities. Journal of Medicinal Chemistry. 2005;48:8194–8208
  107. Rudolph J, Chen L, Majumdar D, et al. Indanylacetic acid derivatives carrying 4-thiazolyl-phenoxy tail groups, a new class of potent PPAR alpha/gamma/delta pan agonists: synthesis, structure-activity relationship, and in vivo efficacy. Journal of Medicinal Chemistry. 2007;50:984–1000

PII: S1521-690X(07)00088-7

doi: 10.1016/j.beem.2007.09.004

Best Practice & Research Clinical Endocrinology & Metabolism
Volume 21, Issue 4 , Pages 687-710 , December 2007

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