The Korean Journal of Physiology and Pharmacology

The Korean Society of Pharmacology (대한약리학회)
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Pharmacological evaluation of HM41322, a novel SGLT1/2 dual inhibitor, in vitro and in vivo

  • Lee, Kyu Hang (Hanmi Research Center, Hanmi Pharmaceutical Co., Ltd) ;
  • Lee, Sang Don (Hanmi Research Center, Hanmi Pharmaceutical Co., Ltd) ;
  • Kim, Namdu (Hanmi Research Center, Hanmi Pharmaceutical Co., Ltd) ;
  • Suh, Kwee Hyun (Hanmi Research Center, Hanmi Pharmaceutical Co., Ltd) ;
  • Kim, Young Hoon (Hanmi Research Center, Hanmi Pharmaceutical Co., Ltd) ;
  • Sim, Sang Soo (College of Pharmacy, Chung-Ang University)
  • Received : 2018.08.11
  • Accepted : 2018.10.29
  • Published : 2019.01.01
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Abstract

HM41322 is a novel oral sodium-glucose cotransporter (SGLT) 1/2 dual inhibitor. In this study, the in vitro and in vivo pharmacokinetic and pharmacologic profiles of HM41322 were compared to those of dapagliflozin. HM41322 showed a 10-fold selectivity for SGLT2 over SGLT1. HM41322 showed an inhibitory effect on SGLT2 similar to dapagliflozin, but showed a more potent inhibitory effect on SGLT1 than dapagliflozin. The maximum plasma HM41322 level after single oral doses at 0.1, 1, and 3 mg/kg were 142, 439, and 1830 ng/ml, respectively, and the $T_{1/2}$ was 3.1 h. HM41322 was rapidly absorbed and reached the circulation within 15 min. HM41322 maximized urinary glucose excretion by inhibiting both SGLT1 and SGLT2 in the kidney. HM41322 3 mg/kg caused the maximum urinary glucose excretion in normoglycemic mice ($19.32{\pm}1.16mg/g$) at 24 h. In normal and diabetic mice, HM41322 significantly reduced glucose excursion. Four-week administration of HM41322 in db/db mice reduced HbA1c in a dose dependent manner. Taken together, HM41322 showed a favorable preclinical profile of postprandial glucose control through dual inhibitory activities against SGLT1 and SGLT2.

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References

  1. American Diabetes Association. Diagnosis and classification of diabetes mellitus. Diabetes Care. 2010;33 Suppl 1:S62-69. https://doi.org/10.2337/dc10-S062
  2. Yamagishi S, Imaizumi T. Diabetic vascular complications: pathophysiology, biochemical basis and potential therapeutic strategy. Curr Pharm Des . 2005;11:2279-2299. https://doi.org/10.2174/1381612054367300
  3. Ceriello A. Postprandial hyperglycemia and diabetes complications: is it time to treat? Diabetes . 2005;54:1-7. https://doi.org/10.2337/diabetes.54.1.1
  4. Maruthur NM, Tseng E, Hutfless S, Wilson LM, Suarez-Cuervo C, Berger Z, Chu Y, Iyoha E, Segal JB, Bolen S. Diabetes medications as monotherapy or metformin-based combination therapy for type 2 diabetes: a systematic review and meta-analysis. Ann Intern Med. 2016;164:740-751. https://doi.org/10.7326/M15-2650
  5. Cefalu WT. Pharmacotherapy for the treatment of patients with type 2 diabetes mellitus: rationale and specific agents. Clin Pharmacol Ther. 2007;81:636-649. https://doi.org/10.1038/sj.clpt.6100156
  6. Kanai Y, Lee WS, You G, Brown D, Hediger MA. The human kidney low affinity $Na^{+}$/glucose cotransporter SGLT2. Delineation of the major renal reabsorptive mechanism for D-glucose. J Clin Invest. 1994;93:397-404. https://doi.org/10.1172/JCI116972
  7. Vallon V, Platt KA, Cunard R, Schroth J, Whaley J, Thomson SC, Koepsell H, Rieg T. SGLT2 mediates glucose reabsorption in the early proximal tubule. J Am Soc Nephrol. 2011;22:104-112. https://doi.org/10.1681/ASN.2010030246
  8. Wright EM, Loo DD, Hirayama BA. Biology of human sodium glucose transporters. Physiol Rev. 2011;91:733-794. https://doi.org/10.1152/physrev.00055.2009
  9. Balen D, Ljubojevic M, Breljak D, Brzica H, Zlender V, Koepsell H, Sabolic I. Revised immunolocalization of the $Na^{+}$-D-glucose cotransporter SGLT1 in rat organs with an improved antibody. Am J Physiol Cell Physiol. 2008;295:C475-489. https://doi.org/10.1152/ajpcell.00180.2008
  10. Rieg T, Masuda T, Gerasimova M, Mayoux E, Platt K, Powell DR, Thomson SC, Koepsell H, Vallon V. Increase in SGLT1-mediated transport explains renal glucose reabsorption during genetic and pharmacological SGLT2 inhibition in euglycemia. Am J Physiol Renal Physiol. 2014;306:F188-193. https://doi.org/10.1152/ajprenal.00518.2013
  11. Wilding JP. The role of the kidneys in glucose homeostasis in type 2 diabetes: clinical implications and therapeutic significance through sodium glucose co-transporter 2 inhibitors. Metabolism. 2014;63:1228-1237. https://doi.org/10.1016/j.metabol.2014.06.018
  12. Mudaliar S, Polidori D, Zambrowicz B, Henry RR. Sodium-glucose cotransporter inhibitors: effects on renal and intestinal glucose transport: from bench to bedside. Diabetes Care. 2015;38:2344-2353. https://doi.org/10.2337/dc15-0642
  13. Gorboulev V, Schurmann A, Vallon V, Kipp H, Jaschke A, Klessen D, Friedrich A, Scherneck S, Rieg T, Cunard R, Veyhl-Wichmann M, Srinivasan A, Balen D, Breljak D, Rexhepaj R, Parker HE, Gribble FM, Reimann F, Lang F, Wiese S, et al . $Na^{+}$-D-glucose cotransporter SGLT1 is pivotal for intestinal glucose absorption and glucosedependent incretin secretion Diabetes. 2012;61:187-196. https://doi.org/10.2337/db11-1029
  14. Abdul-Ghani MA, DeFronzo RA, Norton L. Novel hypothesis to explain why SGLT2 inhibitors inhibit only 30-50% of filtered glucose load in humans. Diabetes. 2013;62:3324-3328. https://doi.org/10.2337/db13-0604
  15. Powell DR, DaCosta CM, Smith M, Doree D, Harris A, Buhring L, Heydorn W, Nouraldeen A, Xiong W, Yalamanchili P, Mseeh F, Wilson A, Shadoan M, Zambrowicz B, Ding ZM. Effect of LX4211 on glucose homeostasis and body composition in preclinical models. J Pharmacol Exp Ther. 2014;350:232-242. https://doi.org/10.1124/jpet.114.214304
  16. Zambrowicz B, Freiman J, Brown PM, Frazier KS, Turnage A, Bronner J, Ruff D, Shadoan M, Banks P, Mseeh F, Rawlins DB, Goodwin NC, Mabon R, Harrison BA, Wilson A, Sands A, Powell DR. 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;92:158-169. https://doi.org/10.1038/clpt.2012.58
  17. Powell DR, Smith MG, Doree DD, Harris AL, Xiong WW, Mseeh F, Wilson A, Gopinathan S, Diaz D, Goodwin NC, Harrison B, Strobel E, Rawlins DB, Carson K, Zambrowicz B, Ding ZM. LP-925219 maximizes urinary glucose excretion in mice by inhibiting both renal SGLT1 and SGLT2. Pharmacol Res Perspect. 2015;3:e00129. https://doi.org/10.1002/prp2.129
  18. Powell DR, DaCosta CM, Gay J, Ding ZM, Smith M, Greer J, Doree D, Jeter-Jones S, Mseeh F, Rodriguez LA, Harris A, Buhring L, Platt KA, Vogel P, Brommage R, Shadoan MK, Sands AT, Zambrowicz B. Improved glycemic control in mice lacking Sglt1 and Sglt2. Am J Physiol Endocrinol Metab. 2013;304:E117-130. https://doi.org/10.1152/ajpendo.00439.2012
  19. Powell DR, Smith M, Greer J, Harris A, Zhao S, DaCosta C, Mseeh F, Shadoan MK, Sands A, Zambrowicz B, Ding ZM. LX4211 increases serum glucagon-like peptide 1 and peptide YY levels by reducing sodium/glucose cotransporter 1 (SGLT1)-mediated absorption of intestinal glucose. J Pharmacol Exp Ther. 2013;345:250-259. https://doi.org/10.1124/jpet.113.203364
  20. Kohler S, Zeller C, Iliev H, Kaspers S. Safety and tolerability of empagliflozin in patients with type 2 diabetes: pooled analysis of phase I-III clinical trials. Adv Ther. 2017;34:1707-1726. https://doi.org/10.1007/s12325-017-0573-0
  21. Karagiannis T, Bekiari E, Tsapas A. Canagliflozin in the treatment of type 2 diabetes: an evidence-based review of its place in therapy. Core Evid. 2017;12:1-10. https://doi.org/10.2147/CE.S109654
  22. Avogaro A, Giaccari A, Fioretto P, Genovese S, Purrello F, Giorgino F, Del Prato S. A consensus statement for the clinical use of the renal sodium-glucose co-transporter-2 inhibitor dapagliflozin in patients with type 2 diabetes mellitus. Expert Rev Clin Pharmacol. 2017;10:763-772. https://doi.org/10.1080/17512433.2017.1322507
  23. Liang Y, Arakawa K, Ueta K, Matsushita Y, Kuriyama C, Martin T, Du F, Liu Y, Xu J, Conway B, Conway J, Polidori D, Ways K, Demarest K. Effect of canagliflozin on renal threshold for glucose, glycemia, and body weight in normal and diabetic animal models. PLoS One. 2012;7:e30555. https://doi.org/10.1371/journal.pone.0030555
  24. Riser Taylor S, Harris KB. The clinical efficacy and safety of sodium glucose cotransporter-2 inhibitors in adults with type 2 diabetes mellitus. Pharmacotherapy. 2013;33:984-999. https://doi.org/10.1002/phar.1303
  25. Liu JJ, Lee T, DeFronzo RA. Why Do SGLT2 inhibitors inhibit only 30-50% of renal glucose reabsorption in humans? Diabetes. 2012;61:2199-2204. https://doi.org/10.2337/db12-0052
  26. Shibazaki T, Tomae M, Ishikawa-Takemura Y, Fushimi N, Itoh F, Yamada M, Isaji M. KGA-2727, a novel selective inhibitor of a highaffinity sodium glucose cotransporter (SGLT1), exhibits antidiabetic efficacy in rodent models. J Pharmacol Exp Ther. 2012;342:288-296. https://doi.org/10.1124/jpet.112.193045
  27. Ikumi Y, Kida T, Sakuma S, Yamashita S, Akashi M. Polymerphloridzin conjugates as an anti-diabetic drug that inhibits glucose absorption through the $Na^{+}$/glucose cotransporter (SGLT1) in the small intestine. J Control Release. 2008;125:42-49. https://doi.org/10.1016/j.jconrel.2007.10.001
  28. 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;12:101-110. https://doi.org/10.1177/1479164114563304
  29. Yoder SM, Yang Q, Kindel TL, Tso P. Differential responses of the incretin hormones GIP and GLP-1 to increasing doses of dietary carbohydrate but not dietary protein in lean rats. Am J Physiol Gastrointest Liver Physiol. 2010;299:G476-485. https://doi.org/10.1152/ajpgi.00432.2009
  30. Vilsboll T, Krarup T, Madsbad S, Holst JJ. Both GLP-1 and GIP are insulinotropic at basal and postprandial glucose levels and contribute nearly equally to the incretin effect of a meal in healthy subjects. Regul Pept . 2003;114:115-121. https://doi.org/10.1016/S0167-0115(03)00111-3
  31. Takebayashi K, Inukai T. Effect of sodium glucose cotransporter 2 inhibitors with low SGLT2/SGLT1 selectivity on circulating glucagon-like peptide 1 levels in type 2 diabetes mellitus. J Clin Med Res. 2017;9:745-753. https://doi.org/10.14740/jocmr3112w
  32. Ferrannini E, Muscelli E, Frascerra S, Baldi S, Mari A, Heise T, Broedl UC, Woerle HJ. Metabolic response to sodium-glucose cotransporter 2 inhibition in type 2 diabetic patients. J Clin Invest. 2014;124:499-508. https://doi.org/10.1172/JCI72227