TS-071 is a novel, potent and selective renal sodium-glucose cotransporter 2 (SGLT2) inhibitor with anti-hyperglycaemic activity

Abstract

Background and purpose: The renal sodium-glucose cotransporter 2 (SGLT2) plays an important role in the reuptake of filtered glucose in the proximal tubule and therefore may be an attractive target for the treatment of diabetes mellitus. This study characterizes the pharmacological profile of TS-071 ((1S)-1,5-anhydro-1-[5-(4-ethoxybenzyl)-2-methoxy-4-methylphenyl]-1-thio-D-glucitol hydrate), a novel SGLT2 inhibitor in vitro and in vivo.

Experimental approach: Inhibition of glucose uptake by TS-071 was studied in CHO-K1 cells stably expressing either human SGLT1 or SGLT2. Single oral dosing studies were performed in rats, mice and dogs to assess the abilities of TS-071 to increase urinary glucose excretion and to lower plasma glucose levels.

Key results: TS-071 inhibited SGLT2 activity in a concentration-dependent manner and was a potent and highly selective inhibitor of SGLT2. Orally administered TS-071 increased urinary glucose excretion in Zucker fatty rats and beagle dogs at doses of 0.3 and 0.03 mg·kg(-1) respectively. TS-071 improved glucose tolerance in Zucker fatty rats without stimulating insulin secretion and reduced hyperglycaemia in streptozotocin (STZ)-induced diabetic rats and db/db mice at a dose of 0.3 mg·kg(-1).

Conclusion and implications: These data indicate that TS-071 is a potent and selective SGLT2 inhibitor that improves glucose levels in rodent models of type 1 and 2 diabetes and may be useful for the treatment for diabetes mellitus.

Figure 1

Chemical structure of TS-071.

Figure 2

Inhibitory effects of TS-071 and phlorizin on hSGLT1 and hSGLT2. Each value shown represents the mean ± SEM of the sodium-dependent α-MG uptake (pmol min⁻¹ per well) from 3-4 experiments.

Figure 3

Effects of TS-071 on plasma glucose and insulin levels after oral glucose loading in Zucker fatty rats. (A) Each value shown represents the mean ± SEM of plasma glucose levels (mmol·L⁻¹) (n = 8). (B) Each value shown represents the mean ± SEM of Δglucose AUC_{0–120 min} (mmol·min L⁻¹). ^##P < 0.01 significantly different from normal control (Student's t-test). *P < 0.05, ***P < 0.001 significantly different from vehicle group (Dunnett's test). (C) Each value shown represents the mean ± SEM of plasma insulin levels (ng·mL⁻¹) (n = 8). (D) Each value shown represents the mean ± SEM of changes in insulin levels (ng·mL⁻¹) from 0 to 15 min. ^###P < 0.001 significantly different from normal control (Welch's t-test). *P < 0.05 significantly different from vehicle group (Dunnett's test). Zucker lean rats were used as normal control group.

Figure 4

Effects of TS-071 on non-fasting plasma glucose levels in STZ-induced diabetic rats. (A) Each value shown represents the mean ± SEM of plasma glucose levels (mmol·L⁻¹) (n = 8). (B) Each value shown represents the mean ± SEM of glucose AUC_{0–8 h} (mmol·h L⁻¹). ^###P < 0.001 significantly different from normal control (Welch's t-test). **P < 0.01, ***P < 0.001 significantly different from vehicle group (Dunnett's test).

Figure 5

Effects of TS-071 on non-fasting plasma glucose levels in db/db mice. (A) Each value shown represents the mean ± SEM of plasma glucose levels (mmol·L⁻¹) (n = 8). (B) Each value shown represents the mean ± SEM of glucose AUC_{0–8 h} (mmol·h L⁻¹). ^###P < 0.001 significantly different from normal control (Welch's t-test). ***P < 0.001 significantly different from vehicle group (Dunnett's test). The db/m mice were used as normal control group.

Figure 6

Effects of TS-071 on plasma glucose levels in normal rats. (A) Each value shown represents the mean ± SEM of non-fasting plasma glucose levels (mmol·L⁻¹) (n = 8). Vehicle group compared with TS-071 groups: Significant effect in two-way repeated measures anova (main effect of dose: P = 0.0238, main effect of time: P < 0.0001, interaction effect: P = 0.8442). Vehicle group compared with glibenclamide group: Significant effect in two-way repeated measures anova (main effect of dose: P < 0.0001, main effect of time: P < 0.0001, interaction effect: P < 0.0001). (B) Each value shown represents the mean ± SEM of fasting plasma glucose levels (mmol·L⁻¹) (n = 8). Vehicle group compared with TS-071 groups: Significant effect in two-way repeated measures anova (main effect of dose: P = 0.0021, main effect of time: P < 0.0001, interaction effect: P < 0.0001). Vehicle group compared with glibenclamide group: Significant effect in two-way repeated measures anova (main effect of dose: P = 0.0766, main effect of time: P < 0.0001, interaction effect: P < 0.0001).