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http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/9391完整後設資料紀錄
| DC 欄位 | 值 | 語言 |
|---|---|---|
| dc.contributor.advisor | 梁碧惠(Pi-Hui Liang) | |
| dc.contributor.author | Ya-Wen Liw | en |
| dc.contributor.author | 劉雅雯 | zh_TW |
| dc.date.accessioned | 2021-05-20T20:20:26Z | - |
| dc.date.available | 2016-10-07 | |
| dc.date.available | 2021-05-20T20:20:26Z | - |
| dc.date.copyright | 2011-10-07 | |
| dc.date.issued | 2011 | |
| dc.date.submitted | 2011-08-11 | |
| dc.identifier.citation | 1. King, H.; Aubert, R. E.; and Herman, W.H. Global burden of diabetes, 1995-2025: prevalence, numerical estimates, and projections. Diabetes Care 1998, 21, 1414-1431.
2. Source: IDF, Diabetes Atlas, 4th edition. 'Diabetic facts' World Diabetes Foundation. http://www.worlddiabetesfoundation.org/composite-35.htm (07.07.2011). 3. Kaiser, N.; Leibowitz, G. J. Glucotoxicity and beta-cell failure in type 2 diabetes mellitus. J. Pediatr. Endo. Metab. 2003, 16, 5-22. 4. Morrish, N. J.; Wang, S. L.; Stevens, L. K.; Fuller, J. H.; Keen, H. Mortality and causes of death in the WHO multinational study of vascular disease in diabetes. Diabetologia 2001, 44, S14–S21. 5. Stratton, I. M.; Adler, A. I.; Neil, H. A.; Matthews, D. R.; Manley, S. E.; Cull, C. A.; Hadden, D.; Turner, R. C.; Holman, R. R. Association of glycemia with macrovascular and microvascular complications of type 2 diabetes (UKPDS 35): prospective observational study. BMJ 2000, 321, 405-412. 6. Bell, D. S. H. Type 2 diabetes mellitus: What is the optimal treatment regimen? Am. J. Med. 2004, 116 (5 Suppl. 1), 23S-29S. 7. Kirpichnikov, D.; McFarlane, S. I.; Sowers, J. R. Metformin: an update. Ann. Intern. Med. 2002, 137, 25-33. 8. Collier, C. A.; Bruce, C. R.; Smith, A. C.; Lopaschuk, G.; Dyck, D. J. Metformin counters the insulin-induced suppression of fatty acid oxidation and stimulation of triacylglycerol storage in rodent skeletal muscle. Am. J. Physiol. Endocrinol. Metab. 2006, 291, E182-E189. 9. Khan, M. A.; St. Peter, J. V.; Xue, J. L. A prospective, randomized comparison of the metabolic effects of pioglitazone or rosiglitazone in patients with type 2 diabetes who were previously treated with troglitazone. Diabetes Care 2002, 25, 708-711. 10. Goldberg, R. B.; Kendall, D. M.; Deeg; Buse, J. B.; Zagar, A. J.; Pinaire, J. A.; Tan, M. H.; Khan, M. A.; PErez, A. T.; Jacober, S. J.; GLAI Study Investigators. A comparison of lipid and glycemic effects of pioglitazone and rosiglitazone in patients with type 2 diabetes and dyslipidemia. Diabetes Care 2005, 28, 1547-1554. 11. Nissen, S. E.; Wolski, K. Effect of rosiglitazone on the risk of myocardial infarction anf death from cardiovascular casues. N. Engl. J. Med. 2007, 356, 2457-2471. 12. Singh, S.; Loke, Y. K.; Furberg, C. D. Long-term risk of cardiovascular events with rosiglitazone: a meta-analysis. JAMA 2007, 298, 1189-1195. 13. Jones, G.; Macklin, J.; Alexander, W. Contraindications to the use of metformin. BMJ 2003, 326, 4-5. 14. Turner, R. C.; Cull, C. A.; Frighi, V.; Holman, R. R. Glycemic control with diet, sulfonylurea, metformin, or insulin in patients with type 2 diabetes mellitus: progressive requirement for multiple therapies (UKPDS 49). UK Prospective Diabetes Study (UKPDS) Group. JAMA 1999, 281, 2005-2012. 15. Brown, G. K. Glucose transporters: structure, function, and consequences of deficiency. J. Inherit. Metab. Dis. 2000, 23, 237-246. 16. Wood, I. S.; Trayhurn, P. Glucose transporters (GLUT and SGLT): expanded families of sugar transport proteins. Br. J. Nutr. 2003, 89, 3-9. 17. Wright, E. M. Renal Na+-glucose contransporters. Am. J. Physiol. Renal Physiol. 2001, 280, F10-F18. 18. Turk, E.; Wright, E. M. Membrane topological motifs in the SGLT contransporter family. J. Membr. Biol. 1997, 159, 1-20. 19. Wright, E. M.; Hirayama, B. A.; Loo, D. F. Active sugar transport in health and disease. J. Intern. Med. 2007, 261, 32-43. 20. Wright, E. M.; Loo, D. F. L.; Hirayama, B. A.; Turk, E. Surprising Versatility of Na+-Glucose Cotransporter: SLC5. Physiology 2004, 19, 370-376. 21. Lee, Y. J.; Han, H. J. Regulatory mechanisms of Na+/glucose cotransporters in renal proximal tubule cells. Kidney Int 2007, 72, S27-S35. 22. Turk, E.; Martin, M. G.; Wright, E. M. Structure of the human Na+/glucose cotransporter gene SGLT1. J. Biol. Chem. 1994, 269, 15204-15209. 23. Kanai, Y.; Lee, W. S.; You, G.; Brown, D.; Hediger, M. A. The human kidney low affinity Na+/glucose transporter SGLT2. Delineation of the major renal reabsorption mechanism for D-glucose. J. Clin. Invest. 1994, 93, 397-404. 24. Abdul-Ghani, M. A.; Norton, L.; DeFronzo, R. A. Role of Sodium-Glucose Cotransporter 2 (SGLT 2) Inhibitors in the Treatment of Type 2 Diabetes. Endocrine Reviews 2011. 25. Valtin, H. Renal function: mechanisms preserving fluid and solute balance in health. Boston: Little, Brown and Company, 1983. 26. Hirayama, B. A.; Lostao, M. P.; Panayotova-Heiermann, M.; Loo, D. D.; Turk, E.; Wright, E. M. Kinetic and specificity differences between rat, human, and rabbit Na+-glucose cotransporters (SGLT-1). Am. J. Physiol. 1996, 270, G919-G926. 27. Gerich, J. E.; Meyer, C.; Woerle, H. J.; Stumvoll, M. Renal gluconeogenesis: its importance in human glucose homeostasis. Diabetes Care 2001, 24, 382-391. 28. White, J. R. Apple Trees to Sodium Glucose Co-Transporter Inhibitors: A Review of SGLT2 Inhibition. Clinical Diabetes 2010, 28, 5-10. 29. Dominguez, J. H.; Camp, K.; Maianu, L.; Feister, H.; Garvey, W. T. Molecular adaptations of GLUT1 and GLUT2 in renal proximal tubules of diabetic rats. Am. J. Physiol. 1994, 266, F283-F290. 30. Dominguez, J. H.; Song, B.; Maianu, L.; Garvey, W. T.; Qulali, M. Gene expression of epithelial glucose transporters: the role of diabetes mellitus. J. Am. Soc. Nephrol. 1994, 5(5 Suppl. 1), S29-S36. 31. Noonan, W. T.; Shapiro, V. M.; Banks, R. O. Renal glucose reabsorption during hypertonic glucose infusion in female streptozotocin-induced diabetic rats. Life Sci. 2001, 68, 2967-2977. 32. Rahmoune, H.; Thompson, P. W.; Ward, J. M.; Smith, C. D.; Hong, G.; Brown, J. Glucose transporters in human renal proximal tubular cells isolated from the urine of patients with non-insulin-dependent diabetes. Diabetes 2005, 54, 3427-3434. 33. Melin, K.; Meeuwisse, G. W. Glucose-galactose malabsorption. A genetic study. Acta. Paediatr. Scand. 1969, 188(Suppl.), 19. 34. Turk, E.; Zabel, B.; Mundlos, S.; Dyer, J.; Wright, E. M. Glucose/galactose malabsorption caused by a defect in the Na+/glucose cotransporter. Nature 1991, 350, 354-356. 35. Santer, R.; Kinner, M.; Lassen, C. L.; Schneppenheim, R.; Eggert, P.; Bald, M.; Brodehl, J.; Daschner, M.; Ehrich, J. H.; Kemper, M.; Li Volti, S.; Neuhaus, T.; Skovby, F.; Swift, P. G.; Schaub, J.; Klaerke, D. Molecular analysis of the SGLT2 gene in patients with renal glucosuria. J. Am. Soc. Nephrol. 2003, 14, 2873-2882. 36. Elsas, L. J.; Rosenberg, L. E. Familial renal glycosuria: a genetic reappraisal of hexose transport by kidney and intestine. J. Clin. Invest. 1969, 48, 1845-1854. 37. Jurczak, M. J.; Lee, H. Y.; Birkenfeld, A. L.; Jornayvaz, F. R.; Frederick, D. W.; Pongratz, R. L.; Zhao, X.; Moeckel, G. W.; Samuel, V. T.; Whaley, J. M.; Shulman, G. I.; Kibbey, R. G. SGLT2 deletion improves glucose homeostasis and preserves pancreatic beta-cell function. Diabetes 2011, 60, 890-898. 38. Kipp, H.; Kinne-Saffran, E.; Bevan, C.; Kinne, R. K. Characteristics of renal Na(+)-D-glucose cotransport in the skate (Raja erinacea) and shark (Squalus acanthias). Am. J. Physiol. 1997, 273, R134-R142. 39. Vick, H.; Diedrich, D. F.; Baumann, K. Reevaluation of renal tubular glucose transport inhibition by phlorizin analogs. Am. J. Physiol. 1973, 224, 552-557. 40. Novakova, R.; Homerova, D.; Kinne, R. K.; Kinne-Saffran, E.; Lin, J. T. Identification of a region critically involved in the interaction of phlorizin with the rabbit sodium-D-glucose cotransporter SGLT1. J. Membr. Biol. 2001, 184, 55-60. 41. Tyagi, N. K.; Kumar, A.; Goyal, P.; Pandey, D.; Siess, W.; Kinne, R. K. D-Glucose-recognition and phlorizin-binding sites in human sodium/D-glucose cotransporter 1 (hSGLT1): a tryptophan scanning study. Biochemistry-Us 2007, 46, 13616-13628. 42. Puntheeranurak, T.; Kasch, M.; Xia, X.; Hinterdorfer, P.; Kinne, R. K. Three surface subdomains form the vestibule of the Na+/glucose cotransporter SGLT1. J. Biol. Chem. 2007, 282, 25222-25230. 43. Althoff, T.; Hentschel, H.; Luig, J.; Schutz, H.; Kasch, M.; Kinne, R. K. Na(+)-D-glucose cotransporter in the kidney of Squalus acanthias: molecular identification and intrarenal distribution. Am. J. Physiol. Regul. Integr. Comp. Physiol. 2006, 290, R1094-R1104. 44. Pajor, A. M.; Randolph, K. M.; Kerner, S. A.; Smith, C. D. Inhibitor binding in the human renal low- and high-affinity Na+/glucose cotransporters. J. Pharmacol. Exp. Ther. 2008, 324, 985-991. 45. Wuthrich, M.; Sterchi, E. E. Human lactase-phlorizin hydrolase expressed in COS-1 cells is proteolytically processed by the lysosomal pathway. FEBS Lett. 1997, 405, 321-327. 46. Leloup, C.; Orosco, M.; Serradas, P.; Nicolaidis, S.; Penicaud, L. Specific inhibition of GLUT2 in arcuate nucleus by antisense oligonucleotides suppresses nervous control of insulin secretion. Brain Res. Mol. Brain Res. 1998, 57, 275-280. 47. Ehrenkranz, J. R.; Lewis, N. G.; Kahn, C. R.; Roth, J. Phlorizin: a review. Diabetes Metab. Res. Rev. 2005, 21, 31-38. 48. Chao, E. C.; Henry, R. R. SGLT2 inhibition--a novel strategy for diabetes treatment. Nat. Rev. Drug Discov. 2010, 9, 551-559. 49. Oku, A.; Ueta, K.; Arakawa, K.; Ishihara, T.; Nawano, M.; Kuronuma, Y.; Matsumoto, M.; Saito, A.; Tsujihara, K.; Anai, M.; Asano, T.; Kanai, Y.; Endou, H. T-1095, an inhibitor of renal Na+-glucose cotransporters, may provide a novel approach to treating diabetes. Diabetes 1999, 48, 1794-1800. 50. Katsuno, K.; Fujimori, Y.; Takemura, Y.; Hiratochi, M.; Itoh, F.; Komatsu, Y.; Fujikura, H.; Isaji, M. Sergliflozin, a novel selective inhibitor of low-affinity sodium glucose cotransporter (SGLT2), validates the critical role of SGLT2 in renal glucose reabsorption and modulates plasma glucose level. J. Pharmacol. Exp. Ther. 2007, 320, 323-330. 51. Hussey, E. K.; Clark, R. V.; Amin, D. M.; Kipnes, M. S.; O'Connor-Semmes, R. L.; O'Driscoll, E. C.; Leong, J.; Murray, S. C.; Dobbins, R. L.; Layko, D.; Nunez, D. J. Single-dose pharmacokinetics and pharmacodynamics of sergliflozin etabonate, a novel inhibitor of glucose reabsorption, in healthy volunteers and patients with type 2 diabetes mellitus. J. Clin. Pharmacol. 2010, 50, 623-635. 52. Fujimori, Y.; Katsuno, K.; Nakashima, I.; Ishikawa-Takemura, Y.; Fujikura, H.; Isaji, M. Remogliflozin etabonate, in a novel category of selective low-affinity sodium glucose cotransporter (SGLT2) inhibitors, exhibits antidiabetic efficacy in rodent models. J. Pharmacol. Exp. Ther. 2008, 327, 268-276. 53. Meng, W.; Ellsworth, B. A.; Nirschl, A. A.; McCann, P. J.; Patel, M.; Girotra, R. N.; Wu, G.; Sher, P. M.; Morrison, E. P.; Biller, S. A.; Zahler, R.; Deshpande, P. P.; Pullockaran, A.; Hagan, D. L.; Morgan, N.; Taylor, J. R.; Obermeier, M. T.; Humphreys, W. G.; Khanna, A.; Discenza, L.; Robertson, J. G.; Wang, A.; Han, S.; Wetterau, J. R.; Janovitz, E. B.; Flint, O. P.; Whaley, J. M.; Washburn, W. N. Discovery of dapagliflozin: a potent, selective renal sodium-dependent glucose cotransporter 2 (SGLT2) inhibitor for the treatment of type 2 diabetes. J. Med. Chem. 2008, 51, 1145-1149. 54. Han, S.; Hagan, D. L.; Taylor, J. R.; Xin, L.; Meng, W.; Biller, S. A.; Wetterau, J. R.; Washburn, W. N.; Whaley, J. M. Dapagliflozin, a selective SGLT2 inhibitor, improves glucose homeostasis in normal and diabetic rats. Diabetes 2008, 57, 1723-1729. 55. Obermeier, M.; Yao, M.; Khanna, A.; Koplowitz, B.; Zhu, M.; Li, W.; Komoroski, B.; Kasichayanula, S.; Discenza, L.; Washburn, W.; Meng, W.; Ellsworth, B. A.; Whaley, J. M.; Humphreys, W. G. In vitro characterization and pharmacokinetics of dapagliflozin (BMS-512148), a potent sodium-glucose cotransporter type II inhibitor, in animals and humans. Drug Metab. Dispos. 2010, 38, 405-414. 56. Kipnes, M. Dapagliflozin: an emerging treatment option in type 2 diabetes. Expert Opin. Investig. Drugs 2009, 18, 327-334. 57. Komoroski, B.; Vachharajani, N.; Feng, Y.; Li, L.; Kornhauser, D.; Pfister, M. Dapagliflozin, a novel, selective SGLT2 inhibitor, improved glycemic control over 2 weeks in patients with type 2 diabetes mellitus. Clin. Pharmacol. Ther. 2009, 85, 513-519. 58. List, J. F.; Woo, V.; Morales, E.; Tang, W.; Fiedorek, F. T. Sodium-glucose cotransport inhibition with dapagliflozin in type 2 diabetes. Diabetes Care 2009, 32, 650-657. 59. Wilding, J. P.; Norwood, P.; T'Joen, C.; Bastien, A.; List, J. F.; Fiedorek, F. T. A study of dapagliflozin in patients with type 2 diabetes receiving high doses of insulin plus insulin sensitizers: applicability of a novel insulin-independent treatment. Diabetes Care 2009, 32, 1656-16562. 60. Bailey, C. J.; Gross, J. L.; Pieters, A.; Bastien, A.; List, J. F. Effect of dapagliflozin in patients with type 2 diabetes who have inadequate glycaemic control with metformin: a randomised, double-blind, placebo-controlled trial. Lancet 2010, 375, 2223-2233. 61. Wilding, J. P. H.; Woo, V.; Soler, N. G.; Pahor, A.; Sugg, J.; Parikh, S. Dapagliflozin in patients with Type 2 diabetes poorly controlled on insulin therapy - efficacy of a novel insulin-independent treatment. Diabetes 2010, 59(Suppl. 1), A21-A22 (Abstract 78-OR) 62. Strojek, K.; Hruba, V.; Elze, M.; Langkilde, A.; Parikh, S. Efficacy and safety of dapagliflozin in patients with Type 2 diabetes mellitus and inadequate glycaemic control on glimepiride monotherapy. Diabetologia 2010, 53(Suppl. 1). Abstract 870 S347. 63. Nauck, M.; Del Prato, S.; Rohwedder, K.; Elze, M.; Parikh, S. Dapagliflozin vs glipizide in patients with Type 2 diabetes mellitus inadequately controlled on metformin: 52-week results of a double-blind, randomized, controlled trial. Diabetologia 2010, 53(Suppl. 1), Abstract 241. 64. 'Dapagliflozin' ClinicalTrials.gov. http://clinicaltrials.gov/ct2/results?term=dapagliflozin (05.07.2011). 65. Rosenstock J.; Arbit, D.; Usiskin, K.; Capuano, G.; Canovatchel, W. Canagliflozin, an inhibitor od sodium-glucose co-transporter 2 (SGLT2), improves glycemic contorl and lowers bidy weight in subjects with Type 2 diabetes (T2D) on metformin. Diabetes 2010, 59(Suppl. 1), A21 (Abstract 0077-OR). 66. 'Canagliflozin' ClinicalTrials.gov. http://clinicaltrials.gov/ct2/results?term=canagliflozin (05.07.2011) 67. Freiman, J.; Ruff, D. A.; Frazier, K. S.; Combs, K.; Turnage, A.; Shadoan, M.; Powell, D.; Zambrowicz, B.; Brown, P. LX4211, a dual SGLT2/SGLT1 inhibitor, shows rapid and significant improvements in glycemic control over 28 days in patients with type 2 diabetes (T2DM). Diabetes 2010, 59 (Suppl. 1), A511. 68. Mascitti, V.; Maurer, T. S.; Robinson, R. P.; Bian, J.; Boustany-Kari, C. M.; Brandt, T.; Collman, B. M.; Kalgutkar, A. S.; Klenotic, M. K.; Leininger, M. T.; Lowe, A.; Maguire, R. J.; Masterson, V. M.; Miao, Z.; Mukaiyama, E.; Patel, J. D.; Pettersen, J. C.; Preville, C.; Samas, B.; She, L.; Sobol, Z.; Steppan, C. M.; Stevens, B. D.; Thuma, B. A.; Tugnait, M.; Zeng, D.; Zhu, T. Discovery of a clinical candidate from the structurally unique dioxa-bicyclo[3.2.1]octane class of sodium-dependent glucose cotransporter 2 inhibitors. J. Med. Chem. 2011, 54, 2952-2960. 69. Mascitti, V.; Robinson, R. P.; Preville, C.; Thuma, B. A.; Carr, C. L.; Reese, M. R.; Maguire, R. J.; Leininger, M. T.; Lowe, A.; Steppan, C. M. Syntheses of C-5-spirocyclic C-glycoside SGLT2 inhibitors. Tetrahedron Letters 2010, 51, 1880-1883. 70. Robinson, R. P.; Mascitti, V.; Boustany-Kari, C. M.; Carr, C. L.; Foley, P. M.; Kimoto, E.; Leininger, M. T.; Lowe, A.; Klenotic, M. K.; Macdonald, J. I.; Maguire, R. J.; Masterson, V. M.; Maurer, T. S.; Miao, Z.; Patel, J. D.; Preville, C.; Reese, M. R.; She, L.; Steppan, C. M.; Thuma, B. A.; Zhu, T. C-Aryl glycoside inhibitors of SGLT2: Exploration of sugar modifications including C-5 spirocyclization. Bioorg. Med. Chem. Lett. 2010, 20, 1569-1572. 71. Grempler, R.; Thomas, L.; Eckhardt, M.; Himmelsbach, F.; Sauer, A.; Michael, M.; Eickelmann, P. In vitro properties and in vivo effect on unrinary glucose excretion of BI 10773, a novel selective SGLT2 inhibitor. 69th Scientific Sessions 2009, Abstract 521-9. 72. 'BI-10773' ClinicalTrial.gov. http://clinicaltrials.gov/ct2/results?term=BI-10773 (06/07/2011). 73. 'ASP-1941' ClinicalTrial.gov. http://clinicaltrials.gov/ct2/results?term=ASP-1941 (06/07/2011). 74. Bhanot, S.; Murray, S. F.; Booten, S. L.; Chakravarty, K.; Zanardi, T.; Henry, S.; Watts, L. M.; Wancewicz, E. V.; Siwkowsk, A.; Monia, B. P. ISIS 388626, an SGLT2 antisense drug, causes robust and sustained glucosuria in multiple species and is safe and well-tolerated. 69th Scientific Sessions 2009, Abstract 328-OR. 75. Wancewicz, E. V.; Siwkowsk, A.; Meibohm, B.; Yates, C. R.; Pearce, M.; Matson, J.; Booten, S.; Murray, S. F.; Hung, G.; Geary, R. S.; Bhanot, S.; Monia, B. P. 68th Scientific Sessions 2008, Abstract 334-OR. 76. 'ISIS 388626' ClinicalTrial.gov. http://clinicaltrials.gov/ct2/results?term=isis+388626 (06/07/2011). 77. Kakinuma, H.; Oi, T.; Hashimoto-Tsuchiya, Y.; Arai, M.; Kawakita, Y.; Fukasawa, Y.; Iida, I.; Hagima, N.; Takeuchi, H.; Chino, Y.; Asami, J.; Okumura-Kitajima, L.; Io, F.; Yamamoto, D.; Miyata, N.; Takahashi, T.; Uchida, S.; Yamamoto, K. (1S)-1,5-anhydro-1-[5-(4-ethoxybenzyl)-2-methoxy-4-methylphenyl]-1-thio-D- glucitol (TS-071) is a potent, selective sodium-dependent glucose cotransporter 2 (SGLT2) inhibitor for type 2 diabetes treatment. J. Med. Chem. 2010, 53, 3247-3261. 78. Kang, S. Y.; Song, K. S.; Lee, J.; Lee, S. H. Synthesis of pyridazine and thiazole analogs as SGLT2 inhibitors. Bioorg. Med. Chem. 2010, 18, 6069-6079. 79. Lee, J.; Lee, S. H.; Seo, H. J.; Son, E. J.; Jung, M. E.; Lee, M.; Han, H. K.; Kim, J.; Kang, J. Novel C-aryl glucoside SGLT2 inhibitors as potential antidiabetic agents: 1,3,4-Thiadiazolylmethylphenyl glucoside congeners. Bioorg. Med. Chem. 2010, 18, 2178-2194. (81) 80. Lee, J.; Kim, J. Y.; Choi, J.; Lee, S. H.; Kim, J. Pyrimidinylmethylphenyl glucoside as novel C-aryl glucoside SGLT2 inhibitors. Bioorg. Med. Chem. Lett. 2010, 20, 7046-7049. 81. Lee, S. H.; Kim, M. J.; Kim, J.; Park, H. J.; Lee, J. Thiazolylmethyl ortho-substituted phenyl glucoside library as novel C-aryl glucoside SGLT2 inhibitors. Eur. J. Med. Chem. 2011, 46, 2662-2675. 82. Morita, H.; Deguchi, J.; Motegi, Y.; Sato, S.; Aoyama, C.; Takeo, J.; Shiro, M.; Hirasawa, Y. Cyclic diarylheptanoids as Na+-glucose cotransporter (SGLT) inhibitors from Acer nikoense. Bioorg. Med. Chem. Lett. 2010, 20, 1070-1074. 83. Kang, S. Y.; Kim, M. J.; Lee, J. S.; Lee, J. Glucosides with cyclic diarylpolynoid as novel C-aryl glucoside SGLT2 inhibitors. Bioorg. Med. Chem. Lett. 2011, 21, 3759-3763. 84. Xu, B.; Lv, B.; Feng, Y.; Xu, G.; Du, J.; Welihinda, A.; Sheng, Z.; Seed, B.; Chen, Y. O-Spiro C-aryl glucosides as novel sodium-dependent glucose co-transporter 2 (SGLT2) inhibitors. Bioorg. Med. Chem. Lett. 2009, 19, 5632-5635. 85. Xu, B.; Feng, Y.; Cheng, H.; Song, Y.; Lv, B.; Wu, Y.; Wang, C.; Li, S.; Xu, M.; Du, J.; Peng, K.; Dong, J.; Zhang, W.; Zhang, T.; Zhu, L.; Ding, H.; Sheng, Z.; Welihinda, A.; Roberge, J. Y.; Seed, B.; Chen, Y. C-Aryl glucosides substituted at the 4'-position as potent and selective renal sodium-dependent glucose co-transporter 2 (SGLT2) inhibitors for the treatment of type 2 diabetes. Bioorg. Med. Chem. Lett. 2011. 86. Zhang, W.; Welihinda, A.; Mechanic, J.; Ding, H.; Zhu, L.; Lu, Y.; Deng, Z.; Sheng, Z.; Lv, B.; Chen, Y.; Roberge, J. Y.; Seed, B.; Wang, Y. X. EGT1442, a potent and selective SGLT2 inhibitor, attenuates blood glucose and HbA(1c) levels in db/db mice and prolongs the survival of stroke-prone rats. Pharmacol. Res. 2011, 63, 284-293. 87. Yao, C. H.; Song, J. S.; Chen, C. T.; Yeh, T. K.; Hung, M. S.; Chang, C. C.; Liu, Y. W.; Yuan, M. C.; Hsieh, C. J.; Huang, C. Y.; Wang, M. H.; Chiu, C. H.; Hsieh, T. C.; Wu, S. H.; Hsiao, W. C.; Chu, K. F.; Tsai, C. H.; Chao, Y. S.; Lee, J. C. Discovery of Novel N-β-D-Xylosylindole Derivatives as Sodium-Dependent Glucose Cotransporter 2 (SGLT2) Inhibitors for the Management of Hyperglycemia in Diabetes. J. Med. Chem. 2010, 54, 166-178. 88. Kipnes, M. S. Sodium-glucose cotransporter 2 inhibitors in the treatment of Type 2 diabetes: a review of Phase II and III trials. J. Clin. Invest. 2011, 1, 145-156. 89. Pazur, J. H.; Miskiel, F. J.; Liu, B. The identification of furanose and pyranose ring forms of the reducing units of oligosaccharides. Anal Biochem 1988, 174, 46-53. 90. Saotome, G.; Wong, C. H.; Kanie, O. Combinatorial library of five-membered iminocyclitol and the inhibitory activities against glyco-enzymes. Chem. & Biol. 2001, 8, 1061-1070. 91. Yang, W. B.; Patil, S. S.; Tsai, C. H.; Lin, C. H.; Fang, J. M. The synthesis of L-gulose and L-xylose from D-gluconolactone. Tetrahedron 2002, 58, 253-259. 92. Fuji, K.; Ichikawa, K.; Node, M.; Fujita, E. Hard acid and soft nucleophile system. New efficient method for removal of benzyl protecting group. JOC 1979, 44, 1661-1664. | |
| dc.identifier.uri | http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/9391 | - |
| dc.description.abstract | 目前大多數用於治療第二型糖尿病(T2DM)的藥物，並不足以維持血醣於理想範圍，即糖化血色素(HbA1c)數值小於7%。因此，亟需發展有別於目前治療機轉的其他藥物。第二型鈉依賴葡萄糖轉運蛋白(SGLT2)由672個氨基酸所組成，獨特地表現於腎近端小管S1部分，以高容量，低親和力的方式將大部分存在在腎小球濾液裏的腎糖再吸收， 因此推測抑制SGLT2能夠降低血糖濃度以達到血糖控制的效果。
先導化合物，Dapagliflozin 7，具有碳–芳香環-六環葡萄糖苷之結構，可選擇性與SGLT2結合但不被轉運，是一個活性極高的抑制劑。先前已有研究指出，六環的N-glucosides, S-glucosides, thio-C-glucosides and dioxa-bicyclo-[3.2.1]octane皆對SGLT2有抑制的效果，但並未有文獻針對呋喃葡萄糖苷（水溶液中的糖有1%是由呋喃葡萄糖苷組成的）的結構進行過討論。因此我們設計並合成了一系列由碳-芳香環-D-呋喃葡萄糖苷組成的化合物。兩個關鍵的中間物，分別為D -葡萄糖酸-γ-內酯46為偶聯反應所用及C -苯甲醛-葡萄糖65為格氏反應所用。 利用穩定表達hSGLT1的COS-7細胞，我們針對化合物32a-32r進行了14C-AMG攝取抑制測試；然而結果顯示這些分子在5μM的濃度中，對hSGLT1並無抑制效果。另外，針對hSGLT2的細胞測試仍在進行中。 | zh_TW |
| dc.description.abstract | A wide range of medications available for type 2 diabetes (T2DM) are inadequate to maintain the glycemic control at HbA1c <7%, hence development of novel drug with different mechanism of action is desirable. Type 2 sodium-dependent glucose co-transporter (SGLT2) is a 672-amino acid, high capacity, low affinity transporter express nearly exclusively in the S1 segment of the renal proximal tubule. Since SGLT2 mediates the majority of renal glucose reabsorption from the glomerular filtrate, inhibiting SGLT2 is believed to be able to decrease the glucose level to achieve glycemic control.
Dapagliflozin (7), a leading compound with a structure of C-arylglucoside, can bind to but not be transported by SGLT2, andacts as a potent and selective SGLT2 inhibitor. Various glycoform, such as N-glucosides, S-glucosides, thio-C-glucosides and dioxa-bicyclo-[3.2.1]octane have been studied for their effect on SGLT2 inhibitions but no report was published on glucofuranosides which contain 1% composition of sugars in aqueous solution. Herein, we designed and synthesized a series of novel (1S)-1,4-anhydro-1-C-aryl-D-glucitol derivatives. To get these compounds, 2 key intermediates—perbenzylated D-glucono-gamma-lactone 46 and C-benzylaldehyde glucoside 65, were synthesized and they were sequentially subjected to the coupling reaction and Grignard reaction to afford the desired structures. The inhibitory effect of compounds 32a-32r on the uptake of [14C]-AMG were tested in COS-7 cell stably expressing hSGLT1, the results showed no inhibitory activity of these compounds at 5 μM against hSGLT1. Further study on the cell-based assay of hSGLT2 is still in progress. | en |
| dc.description.provenance | Made available in DSpace on 2021-05-20T20:20:26Z (GMT). No. of bitstreams: 1 ntu-100-R98423027-1.pdf: 12917497 bytes, checksum: 54fc21ac89562e74324ae4e2937f612a (MD5) Previous issue date: 2011 | en |
| dc.description.tableofcontents | Table of Contents………………………………………………………………………………………………………………i
List of Figures…………………………………………………………………………………………………………………iv List of Tables………………………………………………………………………………………………………………………v List of Schemes…………………………………………………………………………………………………………………vi List of Abbreviations………………………………………………………………………………………………vii 1. Introduction…………………………………………………………………………………………………………………1 1.1 Type 2 Diabetes Mellitus (T2DM)……………………………………………………1 1.2 Sodium-Glucose Cotransporter (SGLTs)………………………………………3 1.2.1 Glucose Transporters Description………………………………………………………3 1.2.2 Glucose Reabsorption………………………………………………………………………………………5 1.2.3 Hyperglycemia Effects in SGLT2 & GLUT2 Gene Expression…………………………………………………………………………………………………………………………………7 1.2.4 Genetic Disorders………………………………………………………………………………………………8 1.3 SGLT2 Inhibitors………………………………………………………………………………………………………9 1.3.1 Evolution of SGLT2 Inhibitors: O-glucosides, C-arylglucosides and Other Agents………………………………………………………………………10 A. O-glucosides…………………………………………………………………………………………13 B. C-arylglucosides…………………………………………………………………………………15 C. Other Agents……………………………………………………………………………………………21 D. Newly Designed Agents……………………………………………………………………24 1.3.2 Potential Side Effects and Future Perspective…………………28 1.4 Purpose and Aim………………………………………………………………………………………………………30 2. Results and Discussion………………………………………………………………………………………32 2.1 Proposed Scheme for Synthesis of C-Glucofuranoside Analogues…………………………………………………………………………………………………………………………………32 2.1.1 Synthesis of D-glucono-gamma-lactone…………………………………………33 2.1.2 Synthesis of Aglycones………………………………………………………………………………37 2.1.3 Coupling of D-glucono-gamma-lactone & Biphenyl………………39 2.1.4 Building up Library with Grignard Reaction…………………………42 2.2 Biological Activity……………………………………………………………………………………………46 2.2.1 hSGLT1 In vitro Assay…………………………………………………………………………………47 2.2.2 hSGLT2 In vitro Assay…………………………………………………………………………………48 3. Conclusion………………………………………………………………………………………………………………………49 4. Experimental Section……………………………………………………………………………………………50 4.1 Materials………………………………………………………………………………………………………………………50 4.1.1 Chemistry…………………………………………………………………………………………………………………50 4.1.2 General Instrument and Methods…………………………………………………………52 4.1.3 COS-7 Cell Culture…………………………………………………………………………………………53 4.1.4 Transformation and Isolation of Plasmid DNA………………………53 4.1.5 Digestion and Ligation………………………………………………………………………………54 4.1.6 Transfection & Stable Clone Selection………………………………………54 4.1.7 Western Blot…………………………………………………………………………………………………………55 4.2 Methods……………………………………………………………………………………………………………………………56 4.2.1 Chemistry…………………………………………………………………………………………………………………56 4.2.2 Transformation and Isolation of Plasmid DNA……………………108 4.2.3 Digestion and Ligation……………………………………………………………………………109 4.2.4 Transfection………………………………………………………………………………………………………110 4.2.5 Stable Clone Selection……………………………………………………………………………111 4.2.6 Western Blot………………………………………………………………………………………………………111 5. References……………………………………………………………………………………………………………………112 6. Appendices……………………………………………………………………………………………………………………124 | |
| dc.language.iso | en | |
| dc.title | 合成具有活性，選擇性之鈉依賴型葡萄糖共同運輸通道抑制劑之碳-芳香環-D-呋喃葡萄糖苷作爲治療第二型糖尿病之藥物 | zh_TW |
| dc.title | Synthesis of C-aryl D-glucofuranosides as Potent, Selective Sodium-Dependent Glucose Cotransporter 2 (SGLT2) Inhibitors for Type 2 Diabetes Treatment | en |
| dc.type | Thesis | |
| dc.date.schoolyear | 99-2 | |
| dc.description.degree | 碩士 | |
| dc.contributor.oralexamcommittee | 鄭偉杰(Wei-Chieh Cheng),劉景平(Jing-Ping Liu),許麗卿(Lih-Ching Hsu),林君榮(Chun-Jung Lin) | |
| dc.subject.keyword | 第二型糖尿病,第二型鈉依賴葡萄糖轉運蛋白,dapagliflozin,呋,喃葡萄糖苷,碳-芳香環-D-呋,喃葡萄糖苷, | zh_TW |
| dc.subject.keyword | Type 2 Diabetes Mellitus (T2DM),Sodium Glucose co-transporter 2 (SGLT2),glucofuranosides,(1S)-1,4-anhydro-1-C-aryl-D-glucitol, | en |
| dc.relation.page | 232 | |
| dc.rights.note | 同意授權(全球公開) | |
| dc.date.accepted | 2011-08-11 | |
| dc.contributor.author-college | 醫學院 | zh_TW |
| dc.contributor.author-dept | 藥學研究所 | zh_TW |
| 顯示於系所單位： | 藥學系 | |
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