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抗糖尿病小分子ABHD6抑制剂的研究进展

司良辉, 马惠, 周金培, 张惠斌

司良辉, 马惠, 周金培, 张惠斌. 抗糖尿病小分子ABHD6抑制剂的研究进展[J]. 中国药科大学学报, 2017, 48(2): 125-134. DOI: 10.11665/j.issn.1000-5048.20170201
引用本文: 司良辉, 马惠, 周金培, 张惠斌. 抗糖尿病小分子ABHD6抑制剂的研究进展[J]. 中国药科大学学报, 2017, 48(2): 125-134. DOI: 10.11665/j.issn.1000-5048.20170201
SI Lianghui, MA Hui, ZHOU Jinpei, ZHANG Huibin. Advances in antidiabetic small molecule ABHD6 inhibitors[J]. Journal of China Pharmaceutical University, 2017, 48(2): 125-134. DOI: 10.11665/j.issn.1000-5048.20170201
Citation: SI Lianghui, MA Hui, ZHOU Jinpei, ZHANG Huibin. Advances in antidiabetic small molecule ABHD6 inhibitors[J]. Journal of China Pharmaceutical University, 2017, 48(2): 125-134. DOI: 10.11665/j.issn.1000-5048.20170201

抗糖尿病小分子ABHD6抑制剂的研究进展

Advances in antidiabetic small molecule ABHD6 inhibitors

  • 摘要: 2型糖尿病表现为糖脂代谢紊乱并伴随多脏器慢性损害,已成为威胁人类健康的巨大隐患。α/β水解酶结构域-6(α/β hydrolase domain-6,ABHD6)通过水解单酰甘油,负调控胰岛素的释放。小分子ABHD6抑制剂因其在增强胰岛素敏感性、改善脂肪功能等方面的重要作用而有望成为新一代治疗2型糖尿病的药物。本文介绍了ABHD6的作用机制,根据其结构特点对此类抑制剂的最新研究进展进行综述,并对其构效关系进行分析。
    Abstract: Type 2 diabetes, a glucose and lipid metabolism disorder accompanied by chronic multiple organ damage, has become a huge threat to human health. α/β hydrolase domain-6(ABHD6)regulates the insulin release negatively by hydrolyzing monoacylglycerol. Small molecule ABHD6 inhibitors have been proven to lower blood-glucose and regulates energy homeostasis, which is a potential candidate for the treatment of type 2 diabetes. This paper introduced the ABHD6 signaling pathway and its mechanism, then reviewed the progress of small molecule ABHD6 inhibitors with different structures in recent years, and analyzed the structure activity relationship.
  • [1] Zhao SG,Mugabo Y,Ballentine G,et al.alpha/beta-Hydrolase domain 6 deletion Induces adipose browning and prevents obesity and type 2 diabetes[J].Cell Rep, 2016,14(12):2872-2888.
    [2] Wang XN,Xu B,Zhou JP,et al.Advances of anti-diabetic drugs based on new targets[J].J China Pharm Univ(中国药科大学学报),2015,46(2): 141-152.
    [3] Wei QQ,Zhou JP,Zhang HB,et al.Recent research progress in small molecule AMPK direct activators[J].J China Pharm Univ(中国药科大学学报),2015,46(4): 406-415.
    [4] Thomas G,Betters JL,Lord CC,et al.The serine hydrolase ABHD6 is a critical regulator of the metabolic syndrome[J].Cell Rep, 2013,5(2):508-520.
    [5] Lord CC,Thomas G,Brown JM.Mammalian(ABHD)proteins: lipid metabolizing enzymes at the interface of cell signaling and energy metabolism[J].Biochim Biophys Acta, 2013,1831(4):792-802.
    [6] Marco N,Bauke WD.α/β Hydrolase fold enzymes: the family keeps growing[J].Curr Opin Struct Biol, 1999, 9:732-737.
    [7] Thomas G,Brown AL,Brown JM.In vivo metabolite profiling as a means to identify uncharacterized lipase function: recent success stories within the alpha beta hydrolase domain(ABHD)enzyme family[J].Biochim Biophys Acta, 2014,1841(8):1097-1101.
    [8] Dina NP,Savinainen JR,Jarmo TL.Biochemical and pharmacological characterization of human alpha/beta-hydrolase domain containing 6(ABHD6)and 12(ABHD12)[J].J Lipid Res, 2012,53(11):2413-2424.
    [9] Prentki M,Matschinsky FM,Madiraju SR.Metabolic signaling in fuel-induced insulin secretion[J].Cell Metab, 2013,18(2):162-185.
    [10] Labar G,Wouters J,Lambert DM.A review on the monoacylglycerol lipase: at the interface between fat and endocannabinoid signalling [J].Curr Med Chem, 2010, 17: 2588-2607.
    [11] Kang L,He Z,Xu P,et al.Munc13-1 is required for the sustained release of insulin from pancreatic beta cells[J].Cell Metab,2006,3(6):463-468.
    [12] Prentki M, Madiraju SR. Glycerolipid/free fatty acid cycle and islet beta-cell function in health,obesity and diabetes[J].Mol Cell Endocrinol, 2012,353(1/2):88-100.
    [13] Henquin JC. The dual control of insulin secretion by glucose involves triggering and amplifying pathways in β-cells[J].Diabetes Res Clin Pract, 2011,93:S27-S31.
    [14] Wen J,Ribeiro R,Tanaka M,et al.Activation of CB2 receptor is required for the therapeutic effect of ABHD6 inhibition in experimental autoimmune encephalomyelitis[J].Neuropharmacology,2015,99:196-209.
    [15] Ueda N,Tsuboi K.Discrimination between two endocannabinoids[J].Chem Biol, 2012,19(5):545-547.
    [16] Hu J,Zhu C,Huang M.The endocannabinoid system: a new pharmacological target for obesity treatment [J] ? Neurosci Bull,2009,25(3):153-160.
    [17] Alhouayek M,Masquelier J,Muccioli GG.Controlling 2-arachidonoylglycerol metabolism as an anti-inflammatory strategy[J].Drug Discov Today,2014,19(3):295-304.
    [18] Mulvihill MM,Nomura DK.Therapeutic potential of monoacylglycerol lipase inhibitors[J].Life Sci,2013,92(8/9):492-497.
    [19] Townsend KL,Tseng YH.Brown fat fuel utilization and thermogenesis[J].Trends Endocrinol Metab,2014,25(4):168-177.
    [20] Derosa G,Cicero AF,Angelo DA,et al.Effects of 1-year orlistat treatment compared to placebo on insulin resistance parameters in patients with type 2 diabetes[J].J Clin Pharm Ther,2012,37(2):187-195.
    [21] Marrs WR,Horne EA,Ortega GS,et al.Dual inhibition of alpha/beta-hydrolase domain 6 and fatty acid amide hydrolase increases endocannabinoid levels in neurons[J].J Biol Chem,2011, 286(33):28723-28728.
    [22] Blankman JL,Simon GM,Cravatt BF.A comprehensive profile of brain enzymes that hydrolyze the endocannabinoid 2-arachidonoylglycerol[J].Chem Biol,2007,14(12):1347-1356.
    [23] Chang JW,Cognetta AB,Niphakis MJ,et al.Proteome-wide reactivity profiling identifies diverse carbamate chemotypes tuned for serine hydrolase inhibition[J].ACS Chem Biol,2013,8(7):1590-1599.
    [24] Bowman AL,Makriyannis A.Highly predictive ligand-based pharmacophore and homology models of ABHD6[J].Chem Biol Drug Des,2013,81(3):382-388.
    [25] Tchantchou F,Zhang YM.Selective inhibition of alpha/beta-hydrolase domain 6 attenuates neurodegeneration,alleviates blood brain barrier breakdown,and improves functional recovery in a mouse model of traumatic brain injury[J].J Neurotrauma,2013,30(7):565-579.
    [26] Christian P,Sacco J,Adeli K.Autophagy: emerging roles in lipid homeostasis and metabolic control[J].Biochim Biophys Acta,2013,1831(4):819-824.
    [27] Hsu KL,Tsuboi K,Whitby LR,et al.Development and optimization of piperidyl 1,2,3-triazole ureas as selective chemical probes of endocannabinoid biosynthesis[J].J Med Chem,2013,56(21):8257-8269.
    [28] Hsu KL,Tsuboi K,Adibekian A,et al.DAGLbeta inhibition perturbs a lipid network involved in macrophage inflammatory responses[J].Nat Chem Biol,2012,8(12):999-1007.
    [29] Patel JZ,Nevalainen TJ,Savinainen JR,et al.Optimization of 1,2,5-thiadiazole carbamates as potent and selective ABHD6 inhibitors[J].ChemMedChem,2015,10(2):253-265.
    [30] Patel JZ,Bruchem JV,Laitinen T,et al.Revisiting 1,3,4-oxadiazol-2-ones: utilization in the development of ABHD6 inhibitors[J].Bioorg Med Chem,2015,23(19):6335-6345.
    [31] Janssen FJ,Deng H,Baggelaar MP,et al.Discovery of glycine sulfonamides as dual inhibitors of sn-1-diacylglycerol lipase alpha and alpha/beta-hydrolase domain 6[J].J Med Chem,2014,57(15):6610-6622.
    [32] Murthy MS,Marc P,Erik J,et al.ABHD6 antagonists for promoting browning of white adipose tissue functionality: WO,2015127559A1[P].2015-09-03[2016-12-30] .
    [33] Cisar JS,Grice CA,Jones TK,et al.Carbamate compounds and of making and using same:US,20150018335A1[P].2015-01-15[2016-12-30] .
    [34] Pribasnig MA,Mrak I,Grabner GF,et al.alpha/beta Hydrolase domain-containing 6(ABHD6)degrades the late endosomal/lysosomal lipid bis(monoacylglycero)- phosphate[J].J Biol Chem,2015,290(50):29869-29881.
    [35] Zhao SG,Poursharifi P,Mugabo Y,et al.alpha/beta-Hydrolase domain-6 and saturated long chain monoacylglycerol regulate insulin secretion promoted by both fuel and non-fuel stimuli[J].Mol Metab,2015,4(12):940-950.
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出版历程
  • 刊出日期:  2017-04-24

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