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

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Abstract

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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Acknowledgments

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). https://doi.org/10.1007/s00210-011-0713-z

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Keywords

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