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PPARα激动剂降血脂作用的研究进展

胡越, 许军, 刘燕华, 王增涛, 黄黎敏, 方加龙, 王晨

胡越, 许军, 刘燕华, 王增涛, 黄黎敏, 方加龙, 王晨. PPARα激动剂降血脂作用的研究进展[J]. 中国药科大学学报, 2016, 47(1): 118-124. DOI: 10.11665/j.issn.1000-5048.20160118
引用本文: 胡越, 许军, 刘燕华, 王增涛, 黄黎敏, 方加龙, 王晨. PPARα激动剂降血脂作用的研究进展[J]. 中国药科大学学报, 2016, 47(1): 118-124. DOI: 10.11665/j.issn.1000-5048.20160118
HU Yue, XU Jun, LIU Yanhua, WANG Zengtao, HUANG Liming, FANG Jialong, WANG Chen. Advances in lipid-lowering effect of PPARα agonists[J]. Journal of China Pharmaceutical University, 2016, 47(1): 118-124. DOI: 10.11665/j.issn.1000-5048.20160118
Citation: HU Yue, XU Jun, LIU Yanhua, WANG Zengtao, HUANG Liming, FANG Jialong, WANG Chen. Advances in lipid-lowering effect of PPARα agonists[J]. Journal of China Pharmaceutical University, 2016, 47(1): 118-124. DOI: 10.11665/j.issn.1000-5048.20160118

PPARα激动剂降血脂作用的研究进展

基金项目: 江西省科技支撑计划资助项目(No.20121bbg70022)

Advances in lipid-lowering effect of PPARα agonists

  • 摘要: PPARα是PPARs家族一个重要的亚型,PPARs是一组核激素受体,属于Ⅱ型核受体超家族。PPARα激动剂临床上用于治疗高脂血症。PPARα激动剂主要包括天然型和合成型两大类。其中,合成型PPARα激动剂从结构上可分为苯基并杂环类、酰脲类、酰胺类、苯基GFDA2唑(噻唑)类等。目前已有不少PPARα激动剂被批准用于临床或处于临床研究阶段。本文从PPARα的结构特点及生理功能出发,根据其结构分类,对上述各类PPARα激动剂的研究进展进行了综述。
    Abstract: Peroxisome proliferator-activated receptor α(PPARα)is an important subtype in the PPARs family, which are a group of nuclear hormone receptors belonging to type II nuclear receptor super family. PPARα agonists, which used in the treatment of hyperlipemia in clinic, mainly include natural and synthetic types. According to the structure, the synthetic PPARα agonists can be divided into phenyl-heterocyclic derivatives, ureide derivatives, amide derivatives, phenyloxazole or phenylthiazole derivatives, etc. Up to now, many PPARα agonists have been approved or in clinical development, and a series of novel PPARα agonists with higher activity and selectivity are being developed. This review will summarized the progress in PPARα agonists according to their structural classification.
  • [1] Kersten S.Integrated physiology and systems biology of PPARα[J].Mol Metab,2014,3(4):354-371.
    [2] Zeng ZY,Liao GH,Lu YF,et al.Research progress of PPARα agonists on cardiovascular and cerebrovascular diseases[J].Chin J Med Chem,2014,24(2):147-156.
    [3] Issemann I,Green S.Activation of a member of the steroid hormone receptor superfamily by peroxisome proliferators[J].Nature,1990,347(6294):645-650.
    [4] Gilde AJ,Fruchart JC,Staels B.Peroxisome proliferator-activated receptors at the crossroads of obesity,diabetes,and cardiovascular disease[J].J Am Coll Cardiol,2009,48(9):1-9.
    [5] Esmaeli S,Allameh A,Soleimani M,et al.The role of albumin and PPAR-α in differentiation-dependent change of fatty acid profile during differentiation of mesenchymal stem cells to hepatocyte-like cells[J].Cell Biochem Funct,2014,32(5):410-419.
    [6] Lannutti F,Marrone A,Re N.Prediction of the PPARα agonism of fibrates by combined MM-docking approaches[J].J Mol Graph Model,2011,29:865-875.
    [7] Pawlak M,Lefebvre P,Staels B.Molecular mechanism of PPARα action and its impact on lipid metabolism,inflammation and fibrosis in non-alcoholic fatty liver disease[J].J Hepatol,2015,62(3):1-14.
    [8] Huang J,Das SK,Jha P,et al.The PPARα agonist fenofibrate suppresses B-cell lymphoma in mice by modulating lipid metabolism[J].Biochim Biophys Acta,2013,1831(10):1555-1565.
    [9] Wu C,Jia Y,Lee JH,et al.trans-Caryophyllene is a natural agonistic ligand for peroxisome proliferator-activated receptor-α[J].Bioorg Med Chem Lett,2014,24(14):3168-3174.
    [10] Lee JH,Jun HJ,Hoang MH,et al.Catalposide is a natural agonistic ligand of peroxisome proliferator activated receptor-α[J].Biochem Biophys Res Commun,2012,422(4):568-572.
    [11] Jia Y,Bhuiyan MJ,Jun HJ,et al.Ursolic acid is a PPARα agonist that regulates hepatic lipid metabolism[J].Bioorg Med Chem Lett,2011,21(9):5876-5880.
    [12] Jia Y,Kim JY,Jun HJ,et al.Cyanidin is an agonistic ligand for peroxisome proliferator-activated receptor-alpha reducing hepatic lipid[J].Biochim Biophys Acta,2013,1831(4):698-708.
    [13] Goto T,Takahashi N,Kato S,et al.Bixin activates PPARα and improves obesity-induced abnormalities of carbohydrate and lipid metabolism in mice[J].J Agric Food Chem,2012,60(48):11952-11958.
    [14] Goto T, Kim YI, Funakoshi K, et al. Farnesol, an isoprenoid, improves metabolic abnormalities in mice via both PPARα-dependent and -independent pathways[J].Am J Physiol Endocrinol Metab,2011,301(5):1022-1032.
    [15] Lamers C,Dittrich M,Steri R,et al.Molecular determinants for improved activity at PPARα:structure-activity relationship of pirinixic acid derivatives,docking study and site-directed mutagenesis of PPARα[J].Bioorg Med Chem Lett,2014,24(16):4048-4052.
    [16] Jia Y,Kim JH,Nam B,et al.The dipeptide H-Trp-Arg-OH(WR)Is a PPARα agonist and reduces hepatic lipid accumulation in lipid-loaded H4IIE cells[J].Appl Biochem Biotechnol,2015,175(2):1211-1220.
    [17] Shi GQ,Dropinski JF,Zhang Y,et al.Novel 2,3-dihydrobenzofuran-2-carboxylic acids:highly potent and subtype-selective PPARα agonists with potent hypolipidemic activity[J].J Med Chem,2005,48(17):5589-5599.
    [18] Desai RC, Metzger E, Santini C, et al. Design and synthesis of potent and subtype-selective PPARα agonists[J].Bioorg Med Chem Lett,2006,16(6):1673-1678.
    [19] Fruchart JC.Selective peroxisome proliferator-activated receptor α modulators(SPPARMα):the next generation of peroxisome proliferator-activated receptor α-agonists[J].Cardiovasc Diabetol.,2013,12(82):2-8.
    [20] Liu ZM,Hu M,Chan P,et al.Early investigational drugs targeting PPAR-α for the treatment of metabolic disease[J].Expert Opin Investig Drugs,2015,24(5):611-621.
    [21] Sahebkar A, Chew GT, Watts GF. New peroxisome proliferator-activated receptor agonists:potential treatments for atherogenic dyslipidemia and non-alcoholic fatty liver disease[J].Expert Opin Pharmacother,2014,15(4):493-503.
    [22] Brown PJ,Stuart LW,Hurley KP,et al.Identification of a subtype selective human PPARalpha agonist through parallel-array synthesis[J].Bioorg Med Chem Lett,2001,11(9):1225-1227.
    [23] Solingapuram Sai KK,Kil KE,Tu Z,et al.Synthesis,radiolabeling and initial in vivo evaluation of[11C]KSM-01 for imaging PPARα receptors[J].Bioorg Med Chem Lett,2012,22(19):6233-6236.
    [24] Matthews JM,Chen X,Cryan E,et al.Design and synthesis of indane-ureido-thioisobutyric acids:a novel class of PPARα agonists[J].Bioorg Med Chem Lett,2007,17(24):6773-6778.
    [25] Miyachi H, Nomura M, Tanase T, et al. Design,synthesis and evaluation of substituted phenylpropanoic acid derivatives as peroxisome proliferator-activated receptor(PPAR)activators:novel human PPARα-selective activators[J].Bioorg Med Chem Lett,2002,12(1):77-80.
    [26] Sierra ML,Beneton V,Boullay AB,et al.Substituted 2-[(4-aminomethyl)phenoxy]-2-methylpropionic acid PPARalpha agonists.1.Discovery of a novel series of potent HDLc raising agents[J].J Med Chem,2007,50(4):685-695.
    [27] Faucher N,Martres P,Laroze A,et al.Design,synthesis and evaluation of trifluoromethane sulfonamide derivatives as new potent and selective peroxisome proliferator-activated receptor alpha agonists[J].Bioorg Med Chem Lett,2008,18(2):710-715.
    [28] Ban S,Kasuga J,Nakagome I,et al.Structure-based design,synthesis,and nonalcoholic steatohepatitis(NASH)-preventive effect of phenylpropanoic acid peroxisome proliferator-activated receptor(PPAR)α-selective agonists[J].Bioorg Med Chem,2011,19:3183-3191.
    [29] Wagner JD,Shadoan MK,Zhang L,et al.A selective peroxisome proliferator-activated receptor alpha agonist,CP-900691,improves plasma lipids,lipoproteins,and glycemic control in diabetic monkeys[J].J Pharmacol Exp Ther,2010,333(3):844-853.
    [30] Askari B,Wietecha T,Hudkins KL,et al.Effects of CP-900691,a novel peroxisome proliferator-activated receptor α,agonist on diabetic nephropathy in the BTBR ob/ob mouse[J].Lab Invest,2014,94(8):851-862.
    [31] Aoki T,Asaki T,Hamamoto T,et al.Discovery of a novel class of 1,3-dioxane-2-carboxylic acid derivatives as subtype-selective peroxisome proliferator-activated receptor alpha(PPARalpha)agonists[J].Bioorg Med Chem Lett,2008,18(6):2128-2132.
    [32] Asaki T,Aoki T,Hamamoto T,et al.Structure-activity studies on 1,3-dioxane-2-carboxylic acid derivatives,a novel class of subtype-selective peroxisome proliferator-activated receptor alpha(PPARalpha)agonists[J].Bioorg Med Chem,2008,16(2):981-994.
    [33] Nomura M,Yumoto K,Shinozaki T,et al.Discovery of cyclic amine-substituted benzoic acids as PPARα agonists[J].Bioorg Med Chem Lett,2012,22(1):334-338.
    [34] Schäfer HL,Linz W,Falk E,et al,AVE8134,a novel potent PPARα agonist,improves lipid profile and glucose metabolism in dyslipidemic mice and type 2 diabetic rats[J].Acta Pharmacol Sin,2012 33(1):82-90.
    [35] Xu Y,Mayhugnd D,Saeed A,et al.Design and synthesis of a potent and selective triazolone-based peroxisome prolife-rator-activated receptor α agonist[J].J Med Chem,2003,46(24):5121-5124.
    [36] Khera AV,Millar JS,Ruotolo G,et al.Potent peroxisome proliferator-activated receptor-α agonist treatment increases cholesterol efflux capacity in humans with the metabolic syndrome[J].Eur Heart J,2015,25(6):291-295.
    [37] Mizuno CS, Ma G, Khan S, et al. Design, synthesis, biological evaluation and docking studies of pterostilbene analogs inside PPAR[J].Bioorg Med Chem,2008,16(7):3800-3808.
    [38] Sauerberg P,Mogensen JP,Jeppesen L,et al.Design of potent PPARalpha agonists[J].Bioorg Med Chem Lett,2007,17(11):3198-3202.
    [39] Pingali H,Jain M,Shah S,et al.Design and synthesis of novel bis-oximinoalkanoic acids as potent PPARalpha agonists[J].Bioorg Med Chem Lett,2010,20(3):1156-1161.
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  • 刊出日期:  2016-02-24

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