Recent Developments in Sodium-Glucose Co-Transporter 2 (SGLT2) Inhibitors as a Valuable Tool in the Treatment of Type 2 Diabetes Mellitus

Author(s): Shubham Kumar, Gopal L. Khatik, Amit Mittal*

Journal Name: Mini-Reviews in Medicinal Chemistry

Volume 20 , Issue 3 , 2020

Become EABM
Become Reviewer

Graphical Abstract:


In today’s world, metabolic disorders are much dominant, and among them, diabetes is causing the highest rate of mortality. There is no cure for diabetes, while treatment could be done either by insulin therapy or oral antidiabetic drug. Oral antidiabetic agents target pathogenic factors like receptors, enzymes, genes and proteins involved in diabetes progression. Among them, recently, sodium-glucose co-transporters (SGLTs) have been recognized for their potential to effectively treat Type 2 diabetes mellitus. SGLTs are classified as SGLT-1 and SGLT-2, and among them, SGLT-2 is a major transporter which is involved in glucose reabsorption. Therefore, targeting SGLTs by its inhibitors could be a better choice to control the blood glucose level. Canagliflozin, dapagliflozin, empagliflozin, ipragliflozin, luseogliflozin, and tofogliflozin are known to be SGLT-2 inhibitors. Herein, we discussed the current and future aspects of the development and applications of SGLT-2 inhibitors.

Keywords: Diabetes, Hyperglycemia, Hypoglycemic agents, Antidiabetic agents, hSGLT2, SGLT2 inhibitors.

Rotella, D.P. Novel “second-generation” approaches for the control of type 2 diabetes. J. Med. Chem., 2004, 47(17), 4111-4112.
[PMID: 15293978]
World Health Organization.. Diabetes Fact Sheet., http://www.who. int/mediacentre/factsheets/fs312/en/
Reusch, J.E.B.; Manson, J.E. Management of Type 2 Diabetes in 2017: Getting to Goal. JAMA, 2017, 317(10), 1015-1016.
[] [PMID: 28249081]
Zimmet, P.Z.; Magliano, D.J.; Herman, W.H.; Shaw, J.E. Diabetes: a 21st century challenge. Lancet Diabetes Endocrinol., 2014, 2(1), 56-64.
[PMID: 24622669]
Bharatam, P.V.; Patel, D.S.; Adane, L.; Mittal, A.; Sundriyal, S. Modeling and informatics in designing anti-diabetic agents. Curr. Pharm. Des., 2007, 13(34), 3518-3530.
[PMID: 18220788]
Kokil, G.R.; Veedu, R.N.; Ramm, G.A.; Prins, J.B.; Parekh, H.S. Type 2 diabetes mellitus: limitations of conventional therapies and intervention with nucleic acid-based therapeutics. Chem. Rev., 2015, 115(11), 4719-4743.
[] [PMID: 25918949]
Kota, B.P.; Huang, T.H.; Roufogalis, B.D. An overview on biological mechanisms of PPARs. Pharmacol. Res., 2005, 51(2), 85-94.
[PMID: 15629253]
Willson, T.M.; Brown, P.J.; Sternbach, D.D.; Henke, B.R. The PPARs: from orphan receptors to drug discovery. J. Med. Chem., 2000, 43(4), 527-550.
[] [PMID: 10691680]
Kumar, R.; Mittal, A.; Ramachandran, U. Design and synthesis of 6-methyl-2-oxo-1,2,3,4-tetrahydro-pyrimidine-5-carboxylic acid derivative as PPARγ activators. Bioorg. Med. Chem. Lett., 2007, 15,17(16), 4613-4618.
Ramachandran, U.; Kumar, R.; Mittal, A. Fine tuning of PPAR ligands for type 2 diabetes and metabolic syndrome. Mini Rev. Med. Chem., 2006, 6(5), 563-573.
Khatik, G.L.; Datusalia, A.K.; Ahsan, W.; Kaur, P.; Vyas, M.; Mittal, A.; Nayak, S.K. A retrospect study on thiazole derivatives as the potential antidiabetic agents in drug discovery and developments. Curr. Drug Discov. Technol., 2018, 15(3), 163-177.
[] [PMID: 28914188]
Chakraborty, R.; Ramanujam, R. Diabetes anti-insulin resistance associated disorders: Disease and the therapy. Curr. Sci., 2002, 83(12), 1533-1538.
Atgié, C.; Faintrenie, G.; Carpéne, C.; Bukowiecki, L.J.; Géloën, A. Effects of chronic treatment with noradrenaline or a specific β3-adrenergic agonist, CL 316 243, on energy expenditure and epididymal adipocyte lipolytic activity in rat. Comp. Biochem. Physiol. A Mol. Integr. Physiol., 1998, 119(2), 629-636.
[] [PMID: 11249012]
Murthy, V.S.; Kulkarni, V.M. Molecular modeling of Protein Tyrosine Phosphates 1B (PTP1B) inhibitors. Bioorg. Med. Chem. Lett., 2002, (10), 897-906.
Deacon, C.F. A review of dipeptidyl peptidase-4 inhibitors. Hot topics from randomized controlled trials. Diabetes Obes. Metab., 2018, 20(Suppl. 1), 34-46.
[] [PMID: 29364584]
Eldar-Finkelman, H.; Argast, G.M.; Foord, O.; Fischer, E.H.; Krebs, E.G. Expression and characterization of glycogen synthase kinase-3 mutants and their effect on glycogen synthase activity in intact cells. Proc. Natl. Acad. Sci. USA, 1996, 93(19), 10228-10233.
[] [PMID: 8816781]
Nikoulina, S.E.; Ciaraldi, T.P.; Mudaliar, S.; Carter, L.; Johnson, K.; Henry, R.R. Inhibition of glycogen synthase kinase 3 improves insulin action and glucose metabolism in human skeletal muscle. Diabetes, 2002, 51(7), 2190-2198.
[] [PMID: 12086949]
Merrill, G.F.; Kurth, E.J.; Hardie, D.G.; Winder, W.W. AICA riboside increases AMP-activated protein kinase, fatty acid oxidation, and glucose uptake in rat muscle. Am. J. Physiol., 1997, 273(6), E1107-E1112.
[PMID: 9435525]
Erion, M.D. MBO6322 (CS-917) fructose-1,6-bisphosphatase for controlling gluconeogenesis in Type 2 Diabetes. Proc. Natl. Acad. Sci. USA, 2005, 102, 7970-7975.
[] [PMID: 15911772]
Colca, J.R. Discontinued drug in 2007: renal, endocrine and metabolic drugs. Expert Opin. Investig. Drugs, 2008, 17(11), 1641-1650.
[] [PMID: 18922101]
Barros, R.P.; Machado, U.F.; Gustafsson, J.A. Estrogen receptors: new players in diabetes mellitus. Trends Mol. Med., 2006, 12(9), 425-431.
[] [PMID: 16890492]
Su, H.C.; Hung, L.M.; Chen, J.K. Resveratrol, a red wine antioxidant, possesses an insulin-like effect in streptozotocin-induced diabetic rats. Am. J. Physiol. Endocrinol. Metab., 2006, 290(6), E1339-E1346.
[PMID: 16434553]
Palsamy, P.; Subramanian, S. Resveratrol, a natural phytoalexin, normalizes hyperglycemia in streptozotocin-nicotinamide induced experimental diabetic rats. Biomed. Pharmacother., 2008, 62(9), 598-605.
[] [PMID: 18675532]
Huynh, N.T.; Tayek, J.A. Oral arginine reduces systemic blood pressure in type 2 diabetes: its potential role in nitric oxide generation. J. Am. Coll. Nutr., 2002, 21(5), 422-427.
[PMID: 12356784]
Larsen, C.M.; Faulenbach, M.; Vaag, A.; Vølund, A.; Ehses, J.A.; Seifert, B.; Mandrup-Poulsen, T.; Donath, M.Y. Interleukin-1-receptor antagonist in type 2 diabetes mellitus. N. Engl. J. Med., 2007, 356(15), 1517-1526.
[PMID: 17429083]
Wright, E.M.; Hirayama, B.A.; Loo, D.F. Active sugar transport in health and disease. J. Intern. Med., 2007, 261(1), 32-43.
[PMID: 17222166]
Wright, E.M.; Turk, E. The sodium/glucose cotransport family SLC5. Pflugers Arch., 2004, 447(5), 510-518.
[PMID: 12748858]
Guyton, A.; Hall, J. Urine formation by the kidneys: II tubular processing of the glomerular filtrate.Textbook of Medical Physiology; 11th ed; Guyton, A.; Hall, J., Eds.; Elsevier Saunders: Philadelphia, Pennsylvania, 2006, pp. 327-347.
Wright, E.M.; Loo, D.D.; Hirayama, B.A. Biology of human sodium glucose transporters. Physiol. Rev., 2011, 91(2), 733-794.
[PMID: 21527736]
Vallon, V.; Platt, K.A.; Cunard, R.; Schroth, J.; Whaley, J.; Thomson, S.C.; Koepsell, H.; Rieg, T. SGLT2 mediates glucose reabsorption in the early proximal tubule. J. Am. Soc. Nephrol., 2011, 22(1), 104-112.
[PMID: 20616166]
Barfuss, D.W.; Schafer, J.A. Differences in active and passive glucose transport along the proximal nephron. Am. J. Physiol., 1981, 241(3), F322-F332.
[PMID: 7282931]
Turner, R.J.; Moran, A. Heterogeneity of sodium-dependent D-glucose transport sites along the proximal tubule: evidence from vesicle studies. Am. J. Physiol., 1982, 242(4), F406-F414.
[PMID: 6278960]
Turner, R.J.; Moran, A. Further studies of proximal tubular brush border membrane D-glucose transport heterogeneity. J. Membr. Biol., 1982, 70(1), 37-45.
[PMID: 7186937]
Abdul-Ghani, M.A.; DeFronzo, R.A. Inhibition of renal glucose reabsorption: a novel strategy for achieving glucose control in type 2 diabetes mellitus. Endocr. Pract., 2008, 14(6), 782-790.
[PMID: 18996802]
Meyer, C.; Stumvoll, M.; Nadkarni, V.; Dostou, J.; Mitrakou, A.; Gerich, J. Abnormal renal and hepatic glucose metabolism in type 2 diabetes mellitus. J. Clin. Invest., 1998, 102(3), 619-624.
[PMID: 9691098]
Wright, E.M. Renal Na(+)-glucose cotransporters. Am. J. Physiol. Renal Physiol., 2001, 280(1), F10-F18.
[PMID: 11133510]
Lee, Y.J.; Lee, Y.J.; Han, H.J. Regulatory mechanisms of Na(+)/glucose cotransporters in renal proximal tubule cells. Kidney Int. Suppl., 2007, 106(106), S27-S35.
[PMID: 17653207]
Hummel, C.S.; Lu, C.; Loo, D.D.; Hirayama, B.A.; Voss, A.A.; Wright, E.M. Glucose transport by human renal Na+/D-glucose cotransporters SGLT1 and SGLT2. Am. J. Physiol. Cell Physiol., 2011, 300(1), C14-C21.
[] [PMID: 20980548]
Nauck, M.A. Update on developments with SGLT2 inhibitors in the management of type 2 diabetes. Drug Des. Devel. Ther., 2014, 8, 1335-1380.
[PMID: 25246775]
Meyer, C.; Woerle, H.J.; Dostou, J.M.; Welle, S.L.; Gerich, J.E. Abnormal renal, hepatic, and muscle glucose metabolism following glucose ingestion in type 2 diabetes. Am. J. Physiol. Endocrinol. Metab., 2004, 287(6), E1049-E1056.
[PMID: 15304374]
Grempler, R.; Thomas, L.; Eckhardt, M.; Himmelsbach, F.; Sauer, A.; Sharp, D.E.; Bakker, R.A.; Mark, M.; Klein, T.; Eickelmann, P. Empagliflozin, a novel selective sodium glucose cotransporter-2 (SGLT-2) inhibitor: characterisation and comparison with other SGLT-2 inhibitors. Diabetes Obes. Metab., 2012, 14(1), 83-90.
[] [PMID: 21985634]
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.; Préville, 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(8), 2952-2960.
[] [PMID: 21449606]
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(8), 3247-3261.
[] [PMID: 20302302]
Zambrowicz, B.; Freiman, J.; Brown, P.M.; Frazier, K.S.; Turnage, A.; Bronner, J.; Ruff, D.; Shadoan, M.; Banks, P.; Mseeh, F.; Rawlins, D.B.; Goodwin, N.C.; Mabon, R.; Harrison, B.A.; Wilson, A.; Sands, A.; Powell, D.R. LX4211, a dual SGLT1/SGLT2 inhibitor, improved glycemic control in patients with type 2 diabetes in a randomized, placebo-controlled trial. Clin. Pharmacol. Ther., 2012, 92(2), 158-169.
[PMID: 22739142]
Ehrenkranz, J.R.; Lewis, N.G.; Kahn, C.R.; Roth, J. Phlorizin: a review. Diabetes Metab. Res. Rev., 2005, 21(1), 31-38.
[PMID: 15624123]
Rossetti, L.; Smith, D.; Shulman, G.I.; Papachristou, D.; DeFronzo, R.A. Correction of hyperglycemia with phlorizin normalizes tissue sensitivity to insulin in diabetic rats. J. Clin. Invest., 1987, 79(5), 1510-1515.
[] [PMID: 3571496]
Rossetti, L.; Shulman, G.I.; Zawalich, W.; DeFronzo, R.A. Effect of chronic hyperglycemia on in vivo insulin secretion in partially pancreatectomized rats. J. Clin. Invest., 1987, 80(4), 1037-1044.
[] [PMID: 3308956]
Shannon, J.A.; Fisher, S. The renal tubular reabsorption of glucose in the normal dog. Am. J. Physiol., 1938, 122, 765-774.
Vick, H.; Diedrich, D.F.; Baumann, K. Reevaluation of renal tubular glucose transport inhibition by phlorizin analogs. Am. J. Physiol., 1973, 224(3), 552-557.
[PMID: 4691268]
Thorens, B.; Mueckler, M. Glucose transporters in the 21st Century. Am. J. Physiol. Endocrinol. Metab., 2010, 298(2), E141-E145.
[] [PMID: 20009031]
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(9), 1794-1800.
[] [PMID: 10480610]
Isaji, M. SGLT2 inhibitors: molecular design and potential differences in effect. Kidney Int. Suppl., 2011, 120(120), S14-S19.
[] [PMID: 21358697]
Chao, E.C.; Henry, R.R. SGLT2 inhibition--a novel strategy for diabetes treatment. Nat. Rev. Drug Discov., 2010, 9(7), 551-559.
[PMID: 20508640]
Hardman, T.C.; Dubrey, S.W. Development and potential role of type-2 sodium-glucose transporter inhibitors for management of type 2 diabetes. Diabetes Ther., 2011, 2(3), 133-145.
[PMID: 22127823]
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(5), 513-519.
[] [PMID: 19129749]
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(5), 1145-1149.
[PMID: 18260618]
Nomura, S.; Sakamaki, S.; Hongu, M.; Kawanishi, E.; Koga, Y.; Sakamoto, T.; Yamamoto, Y.; Ueta, K.; Kimata, H.; Nakayama, K.; Tsuda-Tsukimoto, M. Discovey of Canagliflozin, A Novel C- Glycoside with Thiopene Ring, as Sodium-Dependent Cotransporter 2 inhibitor for the treatment of T2DM. J. Med. Chem., 2010, 53(17), 6355-6360.
[PMID: 20690635]
Janssen Pharmaceuticals, Inc.. FDA advisory committee meeting. FDA briefing document. NDA 20402 (canagliflozin).,
Heise, T.; Seewaldt-Becker, E.; Macha, S.; Hantel, S.; Pinnetti, S.; Seman, L.; Woerle, H.J. Safety, tolerability, pharmacokinetics and pharmacodynamics following 4 weeks’ treatment with empagliflozin once daily in patients with type 2 diabetes. Diabetes Obes. Metab., 2013, 15(7), 613-621.
[PMID: 23356556]
Fonseca, V.A.; Ferrannini, E.; Wilding, J.P.; Wilpshaar, W.; Dhanjal, P.; Ball, G.; Klasen, S. Active- and placebo-controlled dose-finding study to assess the efficacy, safety, and tolerability of multiple doses of ipragliflozin in patients with type 2 diabetes mellitus. J. Diabetes Complications, 2013, 27(3), 268-273.
[PMID: 23276620]
Kadokura, T.; Zhang, W.; Krauwinkel, W.; Leeflang, S.; Keirns, J.; Taniuchi, Y.; Nakajo, I.; Smulders, R. Clinical pharmacokinetics and pharmacodynamics of the novel SGLT2 inhibitor ipragliflozin. Clin. Pharmacokinet., 2014, 53(11), 975-988.
[] [PMID: 25316572]
Suzuki, M.; Honda, K.; Fukazawa, M.; Ozawa, K.; Hagita, H.; Kawai, T.; Takeda, M.; Yata, T.; Kawai, M.; Fukuzawa, T.; Kobayashi, T.; Sato, T.; Kawabe, Y.; Ikeda, S. Tofogliflozin a potent and highly specific SGLT2 inhibitor, improves glycemic control in diabetic rats and mice. J. Pharmacol. Exp. Ther., 2012, 341, 692-701.
[PMID: 22410641]
Kaku, K.; Watada, H.; Iwamoto, Y.; Utsunomiya, K.; Terauchi, Y.; Tobe, K.; Tanizawa, Y.; Araki, E.; Ueda, M.; Suganami, H.; Watanabe, D. Tofogliflozin 003 Study Group. Efficacy and safety of monotherapy with the novel sodium/glucose cotransporter-2 inhibitor tofogliflozin in Japanese patients with type 2 diabetes mellitus: a combined Phase 2 and 3 randomized, placebo-controlled, double-blind, parallel-group comparative study. Cardiovasc. Diabetol., 2014, 13, 65-80.
[PMID: 24678906]
Yamamoto, K.; Uchida, S.; Kitano, K.; Fukuhara, N.; Okumura-Kitajima, L.; Gunji, E.; Kozakai, A.; Tomoike, H.; Kojima, N.; Asami, J.; Toyoda, H.; Arai, M.; Takahashi, T.; Takahashi, K. TS-071 is a novel, potent and selective renal sodium-glucose cotransporter 2 (SGLT2) inhibitor with anti-hyperglycaemic activity. Br. J. Pharmacol., 2011, 164(1), 181-191.
[PMID: 21410690]
Lapuerta, P.; Zambrowicz, B.; Strumph, P.; Sands, A. Development of sotagliflozin, a dual sodium-dependent glucose transporter 1/2 inhibitor. Diab. Vasc. Dis. Res., 2015, 12(2), 101-110.
[PMID: 25690134]
Zambrowicz, B.; Ogbaa, I.; Frazier, K.; Banks, P.; Turnage, A.; Freiman, J.; Boehm, K.A.; Ruff, D.; Powell, D.; Sands, A. Effects of LX4211, a dual sodium-dependent glucose cotransporters 1 and 2 inhibitor, on postprandial glucose, insulin, glucagon-like peptide 1, and peptide tyrosine tyrosine in a dose-timing study in healthy subjects. Clin. Ther., 2013, 35(8), 1162-1173.e8.
[] [PMID: 23911260]
Dobbins, R.L.; Greenway, F.L.; Chen, L.; Liu, Y.; Breed, S.L.; Andrews, S.M.; Wald, J.A.; Walker, A.; Smith, C.D. Selective sodium-dependent glucose transporter 1 inhibitors block glucose absorption and impair glucose-dependent insulinotropic peptide release. Am. J. Physiol. Gastrointest. Liver Physiol., 2015, 308(11), G946-G954.
[] [PMID: 25767259]
Sands, A.T.; Zambrowicz, B.P.; Rosenstock, J.; Lapuerta, P.; Bode, B.W.; Garg, S.K.; Buse, J.B.; Banks, P.; Heptulla, R.; Rendell, M.; Cefalu, W.T.; Strumph, P. Sotagliflozin, a dual SGLT1 and SGLT2 inhibitor, as adjunct therapy to insulin in type 1 diabetes. Diabetes Care, 2015, 38(7), 1181-1188.
[PMID: 26049551]
Vasilakou, D.; Karagiannis, T.; Athanasiadou, E.; Mainou, M.; Liakos, A.; Bekiari, E.; Sarigianni, M.; Matthews, D.R.; Tsapas, A. Sodium-glucose cotransporter 2 inhibitors for type 2 diabetes: a systematic review and meta-analysis. Ann. Intern. Med., 2013, 159(4), 262-274.
[] [PMID: 24026259]
SGLT-2 inhibitors in clinical trials. (Accessed May 20, 2018).
SGLT-2 inhibitors in clinical trials. https://pubchem.ncbi.nlm. May 20, 2018)
Zhao, X.; Sun, B.; Zheng, H.; Liu, J.; Qian, L.; Wang, X.; Lou, H. Synthesis and biological evaluation of 6-hydroxyl C-aryl glucoside derivatives as novel sodium glucose co-transporter 2 (SGLT2) inhibitors. Bioorg. Med. Chem. Lett., 2018, 28(12), 2201-2205.
[] [PMID: 29764742]
Cao, X.; Zhang, W.; Yan, X.; Huang, Z.; Zhang, Z.; Wang, P.; Shen, J. Modification on the O-glucoside of Sergliflozin-A: A new strategy for SGLT2 inhibitor design. Bioorg. Med. Chem. Lett., 2016, 26(9), 2170-2173.
[] [PMID: 27025345]
Chu, K.F.; Yao, C.H.; Song, J.S.; Chen, C.T.; Yeh, T.K.; Hsieh, T.C.; Huang, C.Y.; Wang, M.H.; Wu, S.H.; Chang, W.E.; Chao, Y.S.; Lee, J.C. N-Indolylglycosides bearing modifications at the glucose C6-position as sodium-dependent glucose co-transporter 2 inhibitors. Bioorg. Med. Chem., 2016, 24(10), 2242-2250.
[] [PMID: 27075813]
Pan, X.; Huan, Y.; Shen, Z.; Liu, Z. Synthesis and biological evaluation of novel tetrahydroisoquinoline-C-aryl glucosides as SGLT2 inhibitors for the treatment of type 2 diabetes. Eur. J. Med. Chem., 2016, 114, 89-100.
[PMID: 26974378]
Yan, Q.; Ding, N.; Li, Y. Synthesis and biological evaluation of novel dioxa-bicycle C-aryl glucosides as SGLT2 inhibitors. Carbohydr. Res., 2016, 421, 1-8.
[] [PMID: 26735747]
Lee, J.; Kim, J.Y.; Choi, J.; Lee, S.H.; Kim, J.; Lee, J. Pyrimidinylmethylphenyl glucoside as novel C-aryl glucoside SGLT2 inhibitors. Bioorg. Med. Chem. Lett., 2010, 20(23), 7046-7049.
[] [PMID: 20952196]
Kuo, G.H.; Gaul, M.D.; Liang, Y.; Xu, J.Z.; Du, F.; Hornby, P.; Xu, G.; Qi, J.; Wallace, N.; Lee, S.; Grant, E.; Murray, W.V.; Demarest, K. Synthesis and biological evaluation of benzocyclobutane-C-glycosides as potent and orally active SGLT1/SGLT2 dual inhibitors. Bioorg. Med. Chem. Lett., 2018, 28(7), 1182-1187.
[] [PMID: 29523385]
Ding, Y.; Mao, L.; Xu, D.; Xie, H.; Yang, L.; Xu, H.; Geng, W.; Gao, Y.; Xia, C.; Zhang, X.; Meng, Q.; Wu, D.; Zhao, J.; Hu, W. C-Aryl glucoside SGLT2 inhibitors containing a biphenyl motif as potential anti-diabetic agents. Bioorg. Med. Chem. Lett., 2015, 25(14), 2744-2748.
[] [PMID: 26026363]
Zinman, B.; Wanner, C.; Lachin, J.M.; Fitchett, D.; Bluhmki, E.; Hantel, S.; Mattheus, M.; Devins, T.; Johansen, O.E.; Woerle, H.J.; Broedl, U.C.; Inzucchi, S.E. EMPA-REG OUTCOME Investigators. Empagliflozin, Cardiovascular Outcomes, and Mortality in Type 2 Diabetes. N. Engl. J. Med., 2015, 373(22), 2117-2128.
[] [PMID: 26378978]
Kim, Y.; Babu, A.R. Clinical potential of sodium-glucose cotransporter 2 inhibitors in the management of type 2 diabetes. Diabetes Metab. Syndr. Obes., 2012, 5, 313-327.
[PMID: 22977310]
Rosenwasser, R.F.; Sultan, S.; Sutton, D.; Choksi, R.; Epstein, B.J. SGLT-2 inhibitors and their potential in the treatment of diabetes. Diabetes Metab. Syndr. Obes., 2013, 6, 453-467.
[PMID: 24348059]
Geerlings, S.; Fonseca, V.; Castro-Diaz, D.; List, J.; Parikh, S. Genital and urinary tract infections in diabetes: impact of pharmacologically-induced glucosuria. Diabetes Res. Clin. Pract., 2014, 103(3), 373-381.
[PMID: 24529566]
Kaushal, S.; Singh, H.; Thangaraju, P.; Singh, J. Canagliflozin: A Novel SGLT2 Inhibitor for Type 2 Diabetes Mellitus. N. Am. J. Med. Sci., 2014, 6(3), 107-113.
[] [PMID: 24741548]
Scheen, A.J. Pharmacokinetic and pharmacodynamic profile of empagliflozin, a sodium glucose co-transporter 2 inhibitor. Clin. Pharmacokinet., 2014, 53(3), 213-225.
[] [PMID: 24430725]
Rohwedder, K.; Johnsson, E.; Parikh, S. Reduced risk of hypoglycemic events with dapagliflozin vs. glipizide as add-on therapy in type 2 diabetes mellitus: 4-year data from a phase 3 study. Poster presented at 50th Annual meeting of the European Association for the Study of Diabetes.Vienna., 2014. (Accessed May 20, 2018).
Lambers Heerspink, H.J.; de Zeeuw, D.; Wie, L.; Leslie, B.; List, J. Dapagliflozin a glucose-regulating drug with diuretic properties in subjects with type 2 diabetes. Diabetes Obes. Metab., 2013, 15(9), 853-862.
[PMID: 10.1111/dom.12127] [PMID: 23668478]
Lambers Heerspink, H.J.; de Zeeuw, D.; Wie, L.; Leslie, B.; List, J. Dapagliflozin a glucose-regulating drug with diuretic properties in subjects with type 2 diabetes. Diabetes Obes. Metab., 2013, 15(9), 853-862.
[] [PMID: 23668478]
Weir, M.R.; Januszewicz, A.; Gilbert, R.E. Lavalle, Gonzalez, F.J.; Meininger, G. Lower blood pressure (BP) with canagliflozin (cana) in subjects with type 2 diabetes mellitus (T2DM). Diabetes, 2013, 62(Suppl 1), Abstract 1077-P..
Leiter, L.A.; Yoon, K.H.; Arias, P.; Langslet, G.; Xie, J.; Balis, D.A.; Millington, D.; Vercruysse, F.; Canovatchel, W.; Meininger, G. Canagliflozin provides durable glycemic improvements and body weight reduction over 104 weeks versus glimepiride in patients with type 2 diabetes on metformin: a randomized, double-blind, phase 3 study. Diabetes Care, 2015, 38(3), 355-364.
[] [PMID: 25205142]
Sha, S.; Devineni, D.; Ghosh, A.; Polidori, D.; Hompesch, M.; Arnolds, S.; Morrow, L.; Spitzer, H.; Demarest, K.; Rothenberg, P. Pharmacodynamic effects of canagliflozin, a sodium glucose co-transporter 2 inhibitor, from a randomized study in patients with type 2 diabetes. PLoS One, 2014, 9(8) e105638
[PMID: 25166023]
Hach, T.; Gerich, J.; Salsali, A.; Kim, J.; Hantel, S.; Woerle, H.J.; Broedl, U.C. Empagliflozin improves glycaemic parameters and cardiovascular risk factors in patients with type 2 diabetes: pooled data from four pivotal phase III trials. Diabetes, 2013, 62(Suppl. 1), 69.
Nauck, M.; Del Prato, S.; Durán-García, S.; Rohwedder, K.; Langkilde, A.; Sugg, J.; Parikh, S. Durability of dapagliflozin vs. glipizide as add-on therapies in T2DM inadequately controlled on metformin: 4-year data [Abstract]. (Accessed May 20, 2018).
Chino, Y.; Samukawa, Y.; Sakai, S.; Nakai, Y.; Yamaguchi, J.; Nakanishi, T.; Tamai, I. SGLT2 inhibitor lowers serum uric acid through alteration of uric acid transport activity in renal tubule by increased glycosuria. Biopharm. Drug Dispos., 2014, 35(7), 391-404.
[] [PMID: 25044127]
Lytvyn, Y.; Škrtić, M.; Yang, G.K.; Yip, P.M.; Perkins, B.A.; Cherney, D.Z. Glycosuria-mediated urinary uric acid excretion in patients with uncomplicated type 1 diabetes mellitus. Am. J. Physiol. Renal Physiol., 2015, 308(2), F77-F83.
[] [PMID: 25377916]
Ptaszynska, A.; Hardy, E.; Johnsson, E.; Parikh, S.; List, J. Effects of dapagliflozin on cardiovascular risk factors. Postgrad. Med., 2013, 125(3), 181-189.
[] [PMID: 23748519]
Davies, M.J.; Trujillo, A.; Vijapurkar, U.; Damaraju, C.V.; Meininger, G. Effect of canagliflozin on serum uric acid in patients with type 2 diabetes mellitus. Diabetes Obes. Metab., 2015, 17(4), 426-429.
[PMID: 25600248]
Canagliflozin prescribing information, Janssen Pharmaceuticals 2014.
Ptaszynska, A.; Johnsson, K.M.; Parikh, S.J.; de Bruin, T.W.; Apanovitch, A.M.; List, J.F. Safety profile of dapagliflozin for type 2 diabetes: pooled analysis of clinical studies for overall safety and rare events. Drug Saf., 2014, 37(10), 815-829.
[] [PMID: 25096959]
Dapagliflozin prescribing information, AstraZeneca Pharmaceuticals. (Accessed May 20, 2018).
Empagliflozin. U.S. National Institutes of Health. www.clinicaltrials. gov (Accessed May 20, 2018).

Rights & PermissionsPrintExport Cite as

Article Details

Year: 2020
Page: [170 - 182]
Pages: 13
DOI: 10.2174/1389557519666191009163519
Price: $65

Article Metrics

PDF: 26
PRC: 1