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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
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Advances of anti-diabetic drugs based on new targets

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  • 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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