Effect of Ipragliflozin (ASP1941), a Novel Selective Sodium-Dependent Glucose Co-Transporter 2 Inhibitor, on Urinary Glucose Excretion in Healthy Subjects

Abstract

Administration of ipragliflozin was well tolerated and resulted in a rapid, dose-dependent increase in glucosuria. Pharmacodynamic and pharmacokinetic data suggest that ipragliflozin is suitable for prolonged once-daily oral treatment.

A quantitative LC–MS/MS method for determining ipragliflozin, a sodium-glucose co-transporter 2 (SGLT-2) inhibitor, and its application to a pharmacokinetic study in rats

“…t 1/2 , CL/F, and, Vd/F were 7.6 ± 2.0 h, 0.38 ± 0.13 L/h/kg, and, 4.4 ± 2.6 L/kg, respectively, and the plasma concentration of ipragliflozin 24 h after the oral administration of ipragliflozin to rats (22.9 ± 5.2 ng/mL) was determined. These pharmacokinetic parameters in rats were relatively close to those in humans [1,4,12]. These results suggest that the assay method is valuable for evaluating the pharmacokinetics of ipragliflozin in rats.…”

“…1) is a highly potent and selective sodium-dependent glucose co-transporter-2 (SGLT2) inhibitor, a novel class of hypoglycemic agents [1][2][3][4]. SGLT2 inhibitors suppress glucose re-absorption in the proximal tubules of the kidney and promote the urinary excretion of glucose; therefore, SGLT2 inhibitors may reduce blood glucose levels and body weight [1][2][3][4]. Tahara et al previously reported that ipragliflozin improved diabetes/obesity-associated metabolic abnormalities in type 2 diabetic mice, which suggests that ipragliflozin may be valuable in the treatment of type 2 diabetes with metabolic syndrome [5].…”

Chapter 3. SGLT2 Inhibitors in Development

“…The SGLT2 EC 50 SAR was similar to that of analogs of 17; however, the SGLT1 selectivities, which ranged from 100 to 500, were somewhat reduced suggesting that the constraints imposed by the anhydro pyranose structure did not impact SGLT2 affinity but enhanced SGLT1 affinity with the result being diminished SGLT1 selectivity. The Egret/Chengdu group, having been encouraged by the activity of 6-3, also synthesized 6-4 to better assess the potential of this series.…”

“…64 Likewise the SAR for thiazoles as a surrogate central ring was not encouraging. 64 C2 50 was also 1-2 nM, as reference compounds, the Pfizer group systematically evaluated the impact on SGLT2 affinity following changes in substitution for each of the five pyranosyl carbons of glucose. 65 The results summarized in Table 3.4 revealed that modifications of C5 produced relatively minor reductions in SGLT2 affinity.…”

“…29 Inhibitors were assayed for the ability to inhibit [ 14 C]AMG uptake in a protein-free buffer over a 2-hour incubation period. The response curve was fitted to an empirical model to determine the inhibitor concentration at half maximal response, reported as EC 50 . In most instances 17 or phlorizin was included as a standard.…”