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基于新靶点的抗糖尿病药物研究进展

王薪宁, 徐斌, 周金培, 张惠斌

王薪宁, 徐斌, 周金培, 张惠斌. 基于新靶点的抗糖尿病药物研究进展[J]. 中国药科大学学报, 2015, 46(2): 141-152. DOI: 10.11665/j.issn.1000-5048.20150202
引用本文: 王薪宁, 徐斌, 周金培, 张惠斌. 基于新靶点的抗糖尿病药物研究进展[J]. 中国药科大学学报, 2015, 46(2): 141-152. DOI: 10.11665/j.issn.1000-5048.20150202
shu
WANG Xinning, XU Bin, ZHOU Jinpei, ZHANG Huibin. Advances of anti-diabetic drugs based on new targets[J]. Journal of China Pharmaceutical University, 2015, 46(2): 141-152. DOI: 10.11665/j.issn.1000-5048.20150202
Citation: WANG Xinning, XU Bin, ZHOU Jinpei, ZHANG Huibin. Advances of anti-diabetic drugs based on new targets[J]. Journal of China Pharmaceutical University, 2015, 46(2): 141-152. DOI: 10.11665/j.issn.1000-5048.20150202
shu

基于新靶点的抗糖尿病药物研究进展

  • 中国药科大学江苏省抗代谢性疾病药物重点实验室

基金项目: 国家“重大新药创制”科技重大专项资助项目(No.2013ZX09301303-002)；江苏省自然科学基金资助项目(No.BK20141349)

Advances of anti-diabetic drugs based on new targets

摘要

    摘要
  • 摘要: 随着研究者对糖尿病发病机制研究的不断深入，许多治疗糖尿病的新靶点不断被发现和报道，多种抗糖尿病新药(如利格列汀、艾塞那肽、达格列净等)陆续上市，有多个针对不同靶点的新药处于临床后期研究阶段，这些进展将为糖尿病的治疗提供新的手段。G蛋白偶联受体119(GPR119)、G蛋白偶联受体40(GPR40)、G蛋白偶联受体120(GPR120)、单磷酸腺苷活化蛋白激酶(AMPK)、Apelin受体以及糖原合成酶激酶3β(GSK3β)是几类在当前和未来具有研究价值和开发潜力的抗糖尿病药物新靶点。本文总结了这些靶点的作用途径，并对基于这些新靶点的药物及其研发现状进行了综述。
    Abstract: With the deepening of research, different new anti-diabetic drug targets have been discovered and reported, several categories of anti-diabetic drugs(linagliptin, exenatide, dapagliflozin, etc. )have been brought to the market and some new drugs acting on different targets are in late-stage clinical trials. All these progresses provide new means for overcoming diabetes. GPR119, GPR120, GPR40, AMPK, apelin receptor and GSK3β are anti-diabetic targets with great research values in current days and the future. This article reviews the mechanisms, drugs and research advances with respect to the above-mentioned targets.
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  • [1] Hu FB.Globalization of diabetes:the role of diet,lifestyle,and genes[J].Diabetes Care,2011,34(6):1249-1257.
    [2] Mercado AA,Cobo-Vuilleumier N,Martin ES,et al.Emerging therapeutic targets in regenerative medicine for the treatment of diabetes mellitus a patent literature review[J].Recent Pat Regen Med,2013,3(1):56-62.
    [3] Xu SS,Zhang HB,Zhou JP,et al.Advances of new antidiabetic drugs[J].J China Pharm Univ(中国药科大学学报),2011,42(2):97-106.
    [4] Overton HA,Fyfe MC,Reynet C.GPR119,a novel G protein-coupled receptor target for the treatment of type 2 diabetes and obesity[J].Br J Pharmacol,2008,153(Suppl 1):76-81.
    [5] Kotsikorou E,Askar SM.Exploring the binding site of the G protein-coupled receptor GPR119 model using a pair of diastereomers with opposing action[J].Biophys J,2014,106(2):479a.
    [6] Engelstoft MS,Norn C,Hauge M,et al.Structural basis for constitutive activity and agonist-induced activation of the enteroendocrine fat sensor GPR119[J].Br J Pharmacol,2014,171(24):5774-5789.
    [7] Hansen HS,Rosenkilde MM,Holst JJ,et al.GPR119 as a fat sensor[J].Trends Pharmacol Sci,2012,33(7):374-381.
    [8] Soga T, Ohishi T, Matsui T, et al. Lysophosphatidylcholine enhances glucose-dependent insulin secretion via an orphan G-protein-coupled receptor[J].Biochem Biophys Res Commun,2005,326(4):744-751.
    [9] Overton HA,Babbs AJ,Doel SM,et al.Deorphanization of a G protein-coupled receptor for oleoylethanolamide and its use in the discovery of small-molecule hypophagic agents[J].Cell Metab,2006,3(3):167-175.
    [10] Ohishi T,Yoshida S.The therapeutic potential of GPR119 agonists for type 2 diabetes[J].Expert Opin Investig Drugs,2012,21(3):321-328.
    [11] Holst JJ.The physiology of glucagon-like peptide 1[J].Physiol Rev,2007,87(4):1409-1439.
    [12] Shah U.GPR119 agonists:a promising new approach for the treatment of type 2 diabetes and related metabolic disorders[J].Curr Opin Drug Discov Devel,2009,12(4):519-532.
    [13] Buzard DJ,Lehmann J,Han S,et al.GPR119 agonists 2009-2011[J].Pharm Pat Anal,2012,1(3):285-299.
    [14] Song JG,Wherter CA,Ma F,et al.Substituted tetrazol-1-yl-phenoxymethyl-thiazol-2-yl-piperidinyl-pyrimidine salts: US,20110152270A1[P].2011-06-23[2014-12-28] .
    [15] Nunez D,Bush M,Collins D,et al.Gut hormone pharmacology of a novel GPR119 agonist(GSK1292263),metformin,and sitagliptin in type 2 diabetes mellitus:results from two randomized studies[J].PLoS One,2014,9(4):e92494.
    [16] Wacker DA,Wang Y,Broekema M,et al.Discovery of 5-chloro-4-((1-(5-chloropyrimidin-2-yl)piperidin-4-yl)oxy)-1-(2-fluoro-4-(methylsulfonyl)phenyl)pyridin-2(1H)-one(BMS-903452),an antidiabetic clinical candidate targeting GPR119[J].J Med Chem,2014,57(18):7499-7508.
    [17] Semple G,Lehmann J,Wong A,et al.Discovery of a second generation agonist of the orphan G-protein coupled receptor GPR119 with an improved profile[J].Bioorg Med Chem Lett,2012,22(4):1750-1755.
    [18] Kang SU.GPR119 agonists:a promising approach for T2DM treatment? A SWOT analysis of GPR119[J].Drug Discov Today,2013,18(23/24):1309-1315.
    [19] Cornall LM,Mathai ML,Hryciw DH,et al.Is GPR119 agonism an appropriate treatment modality for the safe amelioration of metabolic diseases[J]?Expert Opin Investig Drugs,2013,22(4):487-498.
    [20] Telvekar VN,Kundaikar HS.GPR40 carboxylic acid receptor family and diabetes:a new drug target[J].Curr Drug Targets,2008,9(10):899-910.
    [21] Brownlie R,Mayers RachelM,Pierce JackieA,et al.The long-chain fatty acid receptor,GPR40,and glucolipotoxicity:investigations using GPR40-knockout mice[J].Biochem Soc Trans,2008,36(5):950-954.
    [22] Bharate SB,Nemmani KV,Vishwakarma RA.Progress in the discovery and development of small-molecule modulators of G-protein-coupled receptor40(GPR40/FFA1/FFAR1):an emerging target for type 2 diabetes[J].Expert Opin Ther Pat,2009,19(2):237-264.
    [23] Feng XT,Leng J,Xie Z,et al.GPR40:a therapeutic target for mediating insulin secretion(review)[J].Int J Mol Med,2012,30(6):1261-1266.
    [24] Burant CF.Activation of GPR40 as a therapeutic target for the treatment of type 2 diabetes[J].Diabetes Care,2013,36(Suppl 2):175-179.
    [25] Poitout V,Lin DC.Modulating GPR40:therapeutic promise and potential in diabetes[J].Drug Discov Today,2013,18(23/24):1301-1308.
    [26] Shonberg J,Lopez L,Scammells PJ,et al.Biased agonism at G protein-coupled receptors:the promise and the challenges—a medicinal chemistry perspective[J].Med Res Rev,2014,34(6):1286-1330.
    [27] Mancini AD,Poitout V.The fatty acid receptor FFA1/GPR40 a decade later:how much do we know[J]?Trends Endocrinol Metab,2013,24(8):398-407.
    [28] Violin JD,Crombie AL,Soergel DG,et al.Biased ligands at G-protein-coupled receptors:promise and progress[J].Trends Pharmacol Sci,2014,35(7):308-316.
    [29] Whalen EJ,Rajagopal S,Lefkowitz RJ.Therapeutic potential of beta-arrestin- and G protein-biased agonists[J].Trends Mol Med,2011,17(3):126-139.
    [30] Lead GPR40 agonist bites the dust[J].Nat Rev Drug Discov,2014,13(2):91-91.
    [31] Negoro N, Sasaki S, Mikami S, et al. Discovery of TAK-875: a potent,selective,and orally bioavailable GPR40 agonist[J].ACS Med Chem Lett,2010,1(6):290-294.
    [32] Yabuki C,Komatsu H,Tsujihata Y,et al.A novel antidiabetic drug,fasiglifam/TAK-875,acts as an ago-allosteric modulator of FFAR1[J].PLoS One,2013,8(10):e76280.
    [33] Hamdouchi C.A novel 1,2,3,4-tetrahydroquinoline derivative useful for the treatment of diabetes: WO,2013025424A1[P].2013-02-21[2014-12-28] .
    [34] Houze JB,Zhu L,Sun Y,et al.AMG 837:a potent,orally bioavailable GPR40 agonist[J].Bioorg Med Chem Lett,2012,22(2):1267-1270.
    [35] Luo J,Swaminath G,Brown SP,et al.A potent class of GPR40 full agonists engages the enteroinsular axis to promote glucose control in rodents[J].PLoS One,2012,7(10):e46300.
    [36] Srivastava A,Yano J,Hirozane Y,et al.High-resolution structure of the human GPR40 receptor bound to allosteric agonist TAK-875[J].Nature,2014,513(7516):124-127.
    [37] Wauquier F,Philippe C,Leotoing L,et al.The free fatty acid receptor G protein-coupled receptor 40(GPR40)protects from bone loss through inhibition of osteoclast differentiation[J].J Biol Chem,2013,288(9):6542-6551.
    [38] Flodgren E,Olde B,Meidute-Abaraviciene S,et al.GPR40 is expressed in glucagon producing cells and affects glucagon secretion[J].Biochem Biophys Res Commun,2007,354(1):240-245.
    [39] Ma D,Lu L,Boneva N,et al.Expression of free fatty acid receptor GPR40 in the neurogenic niche of adult monkey hippocampus[J].Hippocampus,2008,18(3):326-333.
    [40] Hara T,Hirasawa A,Ichimura A,et al.Free fatty acid receptors FFAR1 and GPR120 as novel therapeutic targets for metabolic disorders[J].J Pharm Sci,2011,100(9):3594-3601.
    [41] Oh DY,Olefsky JM.Omega 3 fatty acids and GPR120[J].Cell Metab,2012,15(5):564-565.
    [42] Cornall LM,Mathai ML,Hryciw DH,et al.GPR120 agonism as a countermeasure against metabolic diseases[J].Drug Discov Today,2014,19(5):670-679.
    [43] Ichimura A,Hara T,Hirasawa A.Regulation of energy homeostasis via GPR120[J].Front Endocrinol(Lausanne),2014,5:111.
    [44] Talukdar S,Olefsky JM,Osborn O.Targeting GPR120 and other fatty acid-sensing GPCRs ameliorates insulin resistance and inflammatory diseases[J].Trends Pharmacol Sci,2011,32(9):543-550.
    [45] Zhang D,Leung PS.Potential roles of GPR120 and its agonists in the management of diabetes[J].Drug Des Devel Ther,2014,8:1013-1027.
    [46] Halder S,Kumar S,Sharma R.The therapeutic potential of GPR120:a patent review[J].Expert Opin Ther Pat,2013,23(12):1581-1590.
    [47] Briscoe C,Peat A,McKeown S,et al.Pharmacological regulation of insulin secretion in MIN6 cells through the fatty acid receptor GPR40:identification of agonist and antagonist small molecules[J].Br J Pharmacol,2006,148(5):619-628.
    [48] Shimpukade B,Hudson BD,Hovgaard CK,et al.Discovery of a potent and selective GPR120 agonist[J].J Med Chem,2012,55(9):4511-4515.
    [49] Hudson BD,Shimpukade B,Mackenzie AE,et al.The pharmacology of TUG-891,a potent and selective agonist of the free fatty acid receptor 4(FFA4/GPR120),demonstrates both potential opportunity and possible challenges to therapeutic agonism[J].Mol Pharmacol,2013,84(5):710-725.
    [50] Hardie DG.AMPK:a key regulator of energy balance in the single cell and the whole organism[J].Int J Obes(Lond),2008,32(Suppl 4):S7-S12.
    [51] Kemp BE,Oakhill JS,Scott JW.AMPK structure and regulation from three angles[J].Structure,2007,15(10):1161-1163.
    [52] Hardie DG.AMPK:a target for drugs and natural products with effects on both diabetes and cancer[J].Diabetes,2013,62(7):2164-2172.
    [53] Sanders M,Ali ZS,Hegarty B,et al.Defining the mechanism of activation of AMP-activated protein kinase by the small molecule A-769662,a member of the thienopyridone family[J].J Biol Chem,2007,282(45):32539-32548.
    [54] Coughlan KA,Valentine RJ,Ruderman NB,et al.AMPK activation:a therapeutic target for type 2 diabetes[J]?Diabetes Metab Syndr Obes,2014,7:241-253.
    [55] Zhang BB,Zhou G,Li C.AMPK:an emerging drug target for diabetes and the metabolic syndrome[J].Cell Metab,2009,9(5):407-416.
    [56] Steinberg GR,Kemp BE.AMPK in health and disease[J].Physiol Rev,2009,89(3):1025-1078.
    [57] Viollet B, Guiqas B, Leclerc J, et al. AMP-activated protein kinase in the regulation of hepatic energy metabolism:from physiology to therapeutic perspectives[J].Acta Physiol(Oxf),2009,196(1):81-98.
    [58] Liu Y,Dentin R,Chen D,et al.A fasting inducible switch modulates gluconeogenesis via activator/coactivator exchange[J].Nature,2008,456(7219):269-273.
    [59] Shaw R,Lamia K,Vasquez D,et al.The kinase LKB1 mediates glucose homeostasis in liver and therapeutic effects of metformin[J].Science,2005,310(5754):1642-1646.
    [60] Rana S,Blowers EC,Natarajan A.Small molecule adenosine 5′-monophosphate activated protein kinase(AMPK)modulators and human diseases[J].J Med Chem,2014,58(1):2-29.
    [61] Li YY, Yu LF, Zhang LN, et al. Novel small-molecule AMPK activator orally exerts beneficial effects on diabetic db/db mice[J].Toxicol Appl Pharmacol,2013,273(2):325-334.
    [62] Cool B,Zinker B,Chiou W,et al.Identification and characterization of a small molecule AMPK activator that treats key components of type 2 diabetes and the metabolic syndrome[J].Cell Metab,2006,3(6):403-416.
    [63] Yu LF,Li YY,Su MB,et al.Development of novel alkene oxindole derivatives as orally efficacious AMP-activated protein kinase activators[J].ACS Med Chem Lett,2013,4(5):475-480.
    [64] Odowd BF,Heiber M,Chan A,et al.A human gene that shows identity with the gene encoding the angiotensin receptor is located on chromosome 11[J].Gene,1993,136(1/2):437-445.
    [65] Tatemoto K,Hosoya M,Habata Y,et al.Isolation and characterization of a novel endogenous peptide ligand for the human APJ receptor[J].Biochem Biophys Res Commun,1998,251(2):471-476.
    [66] Castan-Laurell I,Dray C,Knauf C,et al.Apelin,a promising target for type 2 diabetes treatment[J]?Trends Endocrinol Metab,2012,23(5):234-241.
    [67] Yue P,Jin H,Aillaud M,et al.Apelin is necessary for the maintenance of insulin sensitivity[J].Am J Physiol Endocrinol Metab,2010,298(1):59-67.
    [68] Yue P,Jin H,Xu S,et al.Apelin decreases lipolysis via Gq,Gi,and AMPK-dependent mechanisms[J].Endocrinology,2011,152(1):59-68.
    [69] Hegarty B,Turner N,Cooney G,et al.Insulin resistance and fuel homeostasis:the role of AMP-activated protein kinase[J].Acta Physiol(Oxf),2009,196(1):129-145.
    [70] Attane C,Foussal C,Le Gonidec S,et al.Apelin treatment increases complete fatty acid oxidation,mitochondrial oxidative capacity,and biogenesis in muscle of insulin-resistant mice[J].Diabetes,2012,61(2):310-320.
    [71] Day RT,Cavaglieri RC,Feliers D.Apelin retards the progression of diabetic nephropathy[J].Am J Physiol Renal Physiol,2012,304(6):788-F800.
    [72] Lu Q,Feng J,Jiang YR.The role of apelin in the retina of diabetic rats[J].PLoS One,2013,8(7):69703.
    [73] Monasterolo LA.Strategies in diabetic nephropathy:apelin is making its way[J].J Physiol,2014,592(Pt 3):423-424.
    [74] Siddiquee K,Hampton J,McAnally D,et al.The apelin receptor inhibits the angiotensin II type 1 receptor via allosteric trans-inhibition[J].Br J Pharmacol,2013,168(5):1104-1117.
    [75] Chen H,Li J,Jiao L,et al.Apelin inhibits the development of diabetic nephropathy by regulating histone acetylation in Akita mouse[J].J Physiol,2014,592(Pt 3):505-521.
    [76] Cavallo MG,Sentinelli F,Barchetta I,et al.Altered glucose homeostasis is associated with increased serum apelin levels in type 2 diabetes mellitus[J].PLoS One,2012,7(12):51236.
    [77] Demydenko G,Kovalyova O.Apelin as a marker of an insulin resistance in patients with essential hypertension[J].Endocrine Abstracts,2014.
    [78] Habchi M,Duvillard L,Cottet V,et al.Circulating apelin is increased in patients with type 1 or type 2 diabetes and is associated with better glycaemic control[J].Clin Endocrinol(Oxf),2014,81(5):696-701.
    [79] Ma WY,Yu TY,Wei JN,et al.Plasma apelin:A novel biomarker for predicting diabetes[J].Clin Chim Acta,2014,435:18-23.
    [80] Oktan MA,Calan M,Calan O,et al.Low apelin levels are associated with a marked increase in risk for development of the gestational diabetes mellitus[J].Endocrine Abstracts,2014,35:383.
    [81] Iturrioz X,Alvear-Perez R,De Mota N,et al.Identification and pharmacological properties of E339-3D6,the first nonpeptidic apelin receptor agonist[J].FASEB J,2010,24(5):1506-1517.
    [82] Margathe JF,Iturrioz X,Alvear-Perez R,et al.Structure-activity relationship studies toward the discovery of selective apelin receptor agonists[J].J Med Chem,2014,57(7):2908-2919.
    [83] Frame S,Cohen P.GSK3 takes centre stage more than 20 years after its discovery[J].Biochem J,2001,359(1):1-16.
    [84] Hernández F,de Barreda E,Fuster-Matanzo A,et al.The role of GSK3 in Alzheimer disease[J].Brain Res Bull,2009,80(4/5):248-250.
    [85] Cohen P,Goedert M.GSK3 inhibitors:development and therapeutic potential[J].Nat Rev Drug Discov,2004,3(6):479-487.
    [86] Martinez A,Castro A,Dorronsoro I,et al.Glycogen synthase kinase 3(GSK-3)inhibitors as new promising drugs for diabetes,neurodegeneration,cancer,and inflammation[J].Med Res Rev,2002,22(4):373-384.
    [87] Gao C,Holscher C,Liu Y,et al.GSK3:a key target for the development of novel treatments for type 2 diabetes mellitus and Alzheimer disease[J].Rev Neurosci,2012,23(1):1-11.
    [88] Vetere A,Choudhary A,Burns SM,et al.Targeting the pancreatic beta-cell to treat diabetes[J].Nat Rev Drug Discov,2014,13(4):278-289.
    [89] Mussmann R,Geese M,Harder F,et al.Inhibition of GSK3 promotes replication and survival of pancreatic beta cells[J].J Biol Chem,2007,282(16):12030-12037.
    [90] Chou DH,Bodycombe NE,Carrinski HA,et al.Small-molecule suppressors of cytokine-induced β-cell apoptosis[J].ACS Chem Biol,2010,5(8):729-734.
    [91] Fornoni A,Pileggi A,Molano RD,et al.Inhibition of c-jun N terminal kinase(JNK)improves functional beta cell mass in human islets and leads to AKT and glycogen synthase kinase-3(GSK-3)phosphorylation[J].Diabetologia,2008,51(2):298-308.
    [92] Stukenbrock H,Mussmann R,Geese M,et al.9-Cyano-1-azapaullone(Cazpaullone),a glycogen synthase kinase-3(GSK-3)inhibitor activating pancreatic β cell protection and replication[J].J Med Chem,2008,51(7):2196-2207.
    [93] Wagman AS,Johnson KW,Bussiere DE.Discovery and development of GSK3 inhibitors for the treatment of type 2 diabetes[J].Curr Pharm Des,2004,10(10):1105-1137.
    [94] Sherwood V.WNT Signaling:an emerging mediator of cancer cell metabolism[J]?Mol Cell Biol,2015,35(1):2-10.
    [95] Vigneron F,Dos-Santos P,Lemoine S,et al.GSK-3β at the crossroads in the signalling of heart preconditioning:implication of mTOR and Wnt pathways[J].Cardiovasc Res,2011,90(1):49-56.
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