Pharmacological profile of ipragliflozin (ASP1941), a novel selective SGLT2 inhibitor, in vitro and in vivo

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The pharmacological profile of ipragliflozin (ASP1941; (1S)-1,5-anhydro-1-C-{3-[(1-benzothiophen-2-yl)methyl]-4-fluorophenyl}-d-glucitol compound with l-proline (1:1)), a novel SGLT2 selective inhibitor, was investigated. In vitro, the potency of ipragliflozin to inhibit SGLT2 and SGLT1 and stability were assessed. In vivo, the pharmacokinetic and pharmacologic profiles of ipragliflozin were investigated in normal mice, streptozotocin-induced type 1 diabetic rats, and KK-Ay type 2 diabetic mice. Ipragliflozin potently and selectively inhibited human, rat, and mouse SGLT2 at nanomolar ranges and exhibited stability against intestinal glucosidases. Ipragliflozin showed good pharmacokinetic properties following oral dosing, and dose-dependently increased urinary glucose excretion, which lasted for over 12 h in normal mice. Single administration of ipragliflozin resulted in dose-dependent and sustained antihyperglycemic effects in both diabetic models. In addition, once-daily ipragliflozin treatment over 4 weeks improved hyperglycemia with a concomitant increase in urinary glucose excretion in both diabetic models. In contrast, ipragliflozin at pharmacological doses did not affect normoglycemia, as was the case with glibenclamide, and did not influence intestinal glucose absorption and electrolyte balance. These results suggest that ipragliflozin is an orally active SGLT2 selective inhibitor that induces sustained increases in urinary glucose excretion by inhibiting renal glucose reabsorption, with subsequent antihyperglycemic effect and a low risk of hypoglycemia. Ipragliflozin has, therefore, the therapeutic potential to treat hyperglycemia in diabetes by increasing glucose excretion into urine.

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  1. Abdul-Ghani MA, DeFronzo RA (2008) Inhibition of renal glucose reabsorption: a novel strategy for achieving glucose control in type 2 diabetes mellitus. Endocr Pract 14:782–790

  2. Andrews WJ, Vasquez B, Nagulesparan M, Klimes I, Foley J, Unger R, Reaven GM (1984) Insulin therapy in obese, non-insulin-dependent diabetes induces improvements in insulin action and secretion that are maintained for two weeks after insulin withdrawal. Diabetes 33:634–642

  3. Baron AD (1998) Postprandial hyperglycaemia and alpha-glucosidase inhibitors. Diabetes Res Clin Pract 40(Suppl):S51–S55

  4. Crofford OB (1995) Diabetes control and complications. Annu Rev Med 46:267–279

  5. Donath MY, Gross DJ, Cerasi E, Kaiser N (1999) Hyperglycemia-induced β-cell apoptosis in pancreatic islets of Psammomys obesus during development of diabetes. Diabetes 48:738–744

  6. Dörner KM (1977) Quantitative determination of lactose, maltose, and sucrose in urine. Eur J Pediatr 126:45–52

  7. Ehrenkranz JR, Lewis NG, Kahn CR, Roth J (2005) Phlorizin: a review. Diabetes Metab Res Rev 21:31–38

  8. Francis J, Zhang J, Farhi A, Carey H, Geller DS (2004) A novel SGLT2 mutation in a patient with autosomal recessive renal glucosuria. Nephrol Dial Transplant 19:2893–2895

  9. Han S, Hagan DL, Taylor JR, Xin L, Meng W, Biller SA, Wetterau JR, Washburn WN, Whaley JM (2008) Dapagliflozin, a selective SGLT2 inhibitor, improves glucose homeostasis in normal and diabetic rats. Diabetes 57:1723–1729

  10. Harmon JS, Gleason CE, Tanaka Y, Poitout V, Robertson RP (2001) Antecedent hyperglycemia, not hyperlipidemia, is associated with increased islet cell triacylglycerol content and decreased insulin gene mRNA level in Zucker Diabetic Fatty rats. Diabetes 50:2481–2486

  11. Idris I, Donnelly R (2009) Sodium–glucose co-transporter-2 inhibitors: an emerging new class of oral antidiabetic drug. Diabetes Obes Metab 11:79–88

  12. Isaji M (2007) Sodium–glucose cotransporter inhibitors for diabetes. Curr Opin Investig Drugs 8:285–292

  13. Jabbour SA, Goldstein BJ (2008) Sodium glucose co-transporter 2 inhibitors: blocking renal tubular reabsorption of glucose to improve glycaemic control in patients with diabetes. Int J Clin Pract 62:1279–1284

  14. Kashiwagi A, Utsuno A, Kazuta K, Yoshida S, Kageyama S (2010) ASP1941, a novel, selective SGLT2 inhibitor, was effective and safe in Japanese healthy volunteers and patients with type 2 diabetes mellitus. Diabetes 59(Suppl 1):A21 (abstract 75-OR)

  15. Katsuno K, Fujimori Y, Takemura Y, Hiratochi M, Itoh F, Komatsu Y, Fujikura H, Isaji M (2007) 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 320:323–330

  16. Komoroski B, Vachharajani N, Feng Y, Li L, Kornhauser D, Pfister M (2009) Dapagliflozin, a novel, selective SGLT2 inhibitor, improved glycemic control over 2 weeks in patients with type 2 diabetes mellitus. Clin Pharmacol Ther 85:513–519

  17. Leese HJ, Semenza G (1973) On the identity between the small intestinal enzymes phlorizin hydrolase and glycosylceramidase. J Biol Chem 248:8170–8173

  18. List JF, Woo V, Morales E, Tang W, Fiedorek FT (2009) Sodium–glucose cotransport inhibition with dapagliflozin in type 2 diabetes. Diabetes Care 32:650–657

  19. Magen D, Sprecher E, Zelikovic I, Skorecki K (2005) A novel missense mutation in SLC5A2 encoding SGLT2 underlies autosomal-recessive renal glucosuria and aminoaciduria. Kidney Int 67:34–41

  20. Masaoka Y, Tanaka Y, Kataoka M, Sakuma S, Yamasita S (2006) Site of drug absorption after oral administration: assessment of membrane permeability and luminal concentration of drugs in each segment of gastrointestinal tract. Eur J Pharm Sci 29:240–250

  21. Matsuo T, Odaka H, Ikeda H (1992) Effect of an intestinal disaccharidase inhibitor (AO-128) on obesity and diabetes. Am J Clin Nutr 55(Suppl):314S–317S

  22. Meng W, Ellsworth BA, Nirschl AA, McCann PJ, Patel M, Girotra RN, Wu G, Sher PM, Morrison EP, Biller SA, Zahler R, Deshpande PP, Pullockaran A, Hagan DL, Morgan N, Taylor JR, Obermeier MT, Humphreys WG, Khanna A, Discenza L, Robertson JG, Wang A, Han S, Wetterau JR, Janovitz EB, Flint OP, Whaley JM, Washburn WN (2008) Discovery of dapagliflozin: a potent, selective renal sodium-dependent glucose cotransporter 2 (SGLT2) inhibitor for the treatment of type 2 diabetes. J Med Chem 51:1145–1149

  23. 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 (1999) T-1095, an inhibitor of renal Na+−glucose cotransporters, may provide a novel approach to treating diabetes. Diabetes 48:1794–1800

  24. Oku A, Ueta K, Arakawa K, Kano-Ishihara T, Matsumoto M, Adachi T, Yasuda K, Tsuda K, Saito A (2000) Antihyperglycemic effect of T-1095 via inhibition of renal Na+-glucose cotransporters in streptozotocin-induced diabetic rats. Biol Pharm Bull 23:1434–1437

  25. Pajor AM, Wright EM (1992) Cloning and functional expression of a mammalian Na+/nucleoside cotransporter. A member of the SGLT family. J Biol Chem 267:3557–3560

  26. Prentki M, Nolan CJ (2006) Islet beta cell failure in type 2 diabetes. J Clin Investig 116:1802–1812

  27. Rossetti L, Shulman GI, Zawalich W, DeFronzo RA (1987a) Effect of chronic hyperglycemia on in vivo insulin secretion in partially pancreatectomized rats. J Clin Investig 80:1037–1044

  28. Rossetti L, Smith D, Shulman GI, Papachristou D, DeFronzo RA (1987b) Correction of hyperglycemia with phlorizin normalizes tissue sensitivity to insulin in diabetic rats. J Clin Investig 79:1510–1515

  29. Santer R, Kinner M, Lassen CL, Schneppenheim R, Eggert P, Bald M, Brodehl J, Daschner M, Ehrich JH, Kemper M, Li Volti S, Neuhaus T, Skovby F, Swift PG, Schaub J, Klaerke D (2003) Molecular analysis of the SGLT2 gene in patients with renal glucosuria. J Am Soc Nephrol 14:2873–2882

  30. Sonnenblick M, Friedlander Y, Rosin AJ (1993) Diuretic-induced hyponatremia. Review and analysis of 129 reported patients. Chest 103:601–606

  31. Stahl M, Berger W (1999) Higher incidence of severe hypoglycaemia leading to hospital admission in type 2 diabetic patients treated with long-acting versus short-acting sulphonylureas. Diabet Med 16:586–590

  32. Tsukada J, Tahara A, Tomura Y, Ki W, Kusayama T, Ishii N, Yatsu T, Uchida W, Taniguchi N, Tanaka A (2001) Effects of YM471, a nonpeptide AVP V1A and V2 receptor antagonist, on human AVP receptor subtypes expressed in CHO cells and oxytocin receptors in human uterine smooth muscle cells. Br J Pharmacol 133:746–754

  33. Turk E, Zabel B, Mundlos S, Dyer J, Wright EM (1991) Glucose/galactose malabsorption caused by a defect in the Na+/glucose cotransporter. Nature 350:354–356

  34. UK Prospective Diabetes Study (UKPDS) Group (1998) Intensive blood–glucose control with sulphonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes (UKPDS 33). Lancet 352:837–853

  35. Vallon V, Richter K, Blantz RC, Thomson S, Osswald H (1999) Glomerular hyperfiltration in experimental diabetes mellitus: potential role of tubular reabsorption. J Am Soc Nephrol 10:2569–2576

  36. van den Heuvel LP, Assink K, Willemsen M, Monnens L (2002) Autosomal recessive renal glucosuria attributable to a mutation in the sodium glucose cotransporter (SGLT2). Hum Genet 111:544–547

  37. Vichayanrat A, Ploybutr S, Tunlakit M, Watanakejorn P (2002) Efficacy and safety of voglibose in comparison with acarbose in type 2 diabetic patients. Diabetes Res Clin Pract 55:99–103

  38. Washburn WN (2009) Evolution of sodium glucose co-transporter 2 inhibitors as anti-diabetic agents. Expert Opin Ther Patents 19:1485–1499

  39. Wells RG, Pajor AM, Kanai Y, Turk E, Wright EM, Hediger MA (1992) Cloning of a human kidney cDNA with similarity to the sodium–glucose cotransporter. Am J Physiol 263:F459–F465

  40. Wright EM (2001) Renal Na+-glucose cotransporters. Am J Physiol Renal Physiol 280:F10–F18

  41. Wright EM, Turk E (2004) The sodium/glucose cotransporter family SLC5. Pflugers Arch 447:510–518

  42. Wright EM, Hirayama BA, Loo DF (2007) Active sugar transport in health and disease. J Intern Med 261:32–43

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The authors acknowledge Drs. Isao Yanagisawa, Seitaro Mutoh, Yasuaki Shimizu, Wataru Uchida, and Shinichi Tsukamoto (Astellas Pharma Inc.) for their valuable comments and continuing encouragement.

Conflict of interest

A. Tahara, E. Kurosaki, M. Yokono, D. Yamajuku, R. Kihara, Y. Hayashizaki, T. Takasu, M. Imamura, L. Qun, M. Sasamata, and M. Shibasaki are employees of Astellas Pharma Inc. H. Tomiyama, Y. Kobayashi, and A. Noda are employees of Kotobuki Pharmaceutical Co. Ltd. Ipragliflozin is in clinical development by Astellas Pharma Inc. and Kotobuki Pharmaceutical Co. Ltd.

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Correspondence to Atsuo Tahara.

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Tahara, A., Kurosaki, E., Yokono, M. et al. Pharmacological profile of ipragliflozin (ASP1941), a novel selective SGLT2 inhibitor, in vitro and in vivo. Naunyn-Schmiedeberg's Arch Pharmacol 385, 423–436 (2012).

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  • Diabetes
  • Hyperglycemia
  • Ipragliflozin
  • Sodium–glucose cotransporter 2
  • Urinary glucose excretion