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SHR3824, a novel selective inhibitor of renal sodium glucose cotransporter 2, exhibits antidiabetic efficacy in rodent models.

Yan PK, Zhang LN, Feng Y, Qu H, Qin L, Zhang LS, Leng Y - Acta Pharmacol. Sin. (2014)

Bottom Line: The purpose of this study was to evaluate SHR3824 as a novel selective SGLT2 inhibitor and to characterize its in vivo effects on glucose homeostasis.SHR3824 potently inhibited human SGLT2 in vitro, but exerted much weak inhibition on human SGLT1 (the IC50 values of SHR3824 against human SGLT2 and SGLT1 were 2.38 and 4324 nmol/L, respectively).SHR3824 is a potent and selective SGLT2 inhibitor and exhibits antidiabetic efficacy in several rodent models, suggesting its potential as a new therapeutic agent for the treatment of type 2 diabetes.

View Article: PubMed Central - PubMed

Affiliation: State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China.

ABSTRACT

Aim: The sodium glucose cotransporter 2 (SGLT2) plays an important role in renal glucose reabsorption, thus serves as a new target for the treatment of diabetes. The purpose of this study was to evaluate SHR3824 as a novel selective SGLT2 inhibitor and to characterize its in vivo effects on glucose homeostasis. The effects of chronic administration of SHR3824 on peripheral insulin sensitivity and pancreatic β-cell function were also investigated.

Methods: The in vitro potency and selectivity of SHR3824 were assessed in HEK293 cells transfected with human SGLT2 or SGLT1. Acute and multi-dose studies were performed on ICR mice, GK rats and db/db mice to assess the ability of SHR3824 to enhance urinary glucose excretion and improve blood glucose levels. 2-Deoxyglucose uptake and insulin immunohistochemical staining were performed in the soleus muscle and pancreas, respectively, of db/db mice. A selective SGLT2 inhibitor BMS512148 (dapagliflozin) was taken as positive control.

Results: SHR3824 potently inhibited human SGLT2 in vitro, but exerted much weak inhibition on human SGLT1 (the IC50 values of SHR3824 against human SGLT2 and SGLT1 were 2.38 and 4324 nmol/L, respectively). Acute oral administration of SHR3824 (0.3, 1.0, 3.0 mg/kg) dose-dependently improved glucose tolerance in ICR mice, and reduced hyperglycemia by increasing urinary glucose excretion in GK rats and db/db mice. Chronic oral administration of SHR3824 (0.3, 1.0, 3.0 mg·kg(-1)·d(-1)) dose-dependently reduced blood glucose and HbA1c levels in GK rats and db/db mice, and significantly increased insulin-stimulated glucose uptake in the soleus muscles and enhanced insulin staining in the islet cells of db/db mice.

Conclusion: SHR3824 is a potent and selective SGLT2 inhibitor and exhibits antidiabetic efficacy in several rodent models, suggesting its potential as a new therapeutic agent for the treatment of type 2 diabetes.

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Related in: MedlinePlus

The chemical structure of SHR3824 (A) and in vitro inhibition of human SGLT2 and SGLT1 by SHR3824 and BMS512148 (B). Data are presented as the mean of two experiments. SGLT1 or SGLT2 expression plasmids were transfected into HEK293 cells. An AMG uptake experiment was performed using transiently transfected cells, and the 95% confidence limits of the IC50 values for each SGLT were calculated.
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fig1: The chemical structure of SHR3824 (A) and in vitro inhibition of human SGLT2 and SGLT1 by SHR3824 and BMS512148 (B). Data are presented as the mean of two experiments. SGLT1 or SGLT2 expression plasmids were transfected into HEK293 cells. An AMG uptake experiment was performed using transiently transfected cells, and the 95% confidence limits of the IC50 values for each SGLT were calculated.

Mentions: SHR3824 ((1R,2S,3S,4R,5R)-5-(4-Chloro-3-(4-ethoxy-3-fluorobenzyl)phenyl)-1-(hydroxymethyl)-6,8-dioxabicyclo[3.2.1]octane-2,3,4-triol, Figure 1A) and dapagliflozin (BMS512148) were synthesized by the Jiangsu Hengrui Pharmaceutical Co, Ltd (Lianyungang, China).


SHR3824, a novel selective inhibitor of renal sodium glucose cotransporter 2, exhibits antidiabetic efficacy in rodent models.

Yan PK, Zhang LN, Feng Y, Qu H, Qin L, Zhang LS, Leng Y - Acta Pharmacol. Sin. (2014)

The chemical structure of SHR3824 (A) and in vitro inhibition of human SGLT2 and SGLT1 by SHR3824 and BMS512148 (B). Data are presented as the mean of two experiments. SGLT1 or SGLT2 expression plasmids were transfected into HEK293 cells. An AMG uptake experiment was performed using transiently transfected cells, and the 95% confidence limits of the IC50 values for each SGLT were calculated.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC4814034&req=5

fig1: The chemical structure of SHR3824 (A) and in vitro inhibition of human SGLT2 and SGLT1 by SHR3824 and BMS512148 (B). Data are presented as the mean of two experiments. SGLT1 or SGLT2 expression plasmids were transfected into HEK293 cells. An AMG uptake experiment was performed using transiently transfected cells, and the 95% confidence limits of the IC50 values for each SGLT were calculated.
Mentions: SHR3824 ((1R,2S,3S,4R,5R)-5-(4-Chloro-3-(4-ethoxy-3-fluorobenzyl)phenyl)-1-(hydroxymethyl)-6,8-dioxabicyclo[3.2.1]octane-2,3,4-triol, Figure 1A) and dapagliflozin (BMS512148) were synthesized by the Jiangsu Hengrui Pharmaceutical Co, Ltd (Lianyungang, China).

Bottom Line: The purpose of this study was to evaluate SHR3824 as a novel selective SGLT2 inhibitor and to characterize its in vivo effects on glucose homeostasis.SHR3824 potently inhibited human SGLT2 in vitro, but exerted much weak inhibition on human SGLT1 (the IC50 values of SHR3824 against human SGLT2 and SGLT1 were 2.38 and 4324 nmol/L, respectively).SHR3824 is a potent and selective SGLT2 inhibitor and exhibits antidiabetic efficacy in several rodent models, suggesting its potential as a new therapeutic agent for the treatment of type 2 diabetes.

View Article: PubMed Central - PubMed

Affiliation: State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China.

ABSTRACT

Aim: The sodium glucose cotransporter 2 (SGLT2) plays an important role in renal glucose reabsorption, thus serves as a new target for the treatment of diabetes. The purpose of this study was to evaluate SHR3824 as a novel selective SGLT2 inhibitor and to characterize its in vivo effects on glucose homeostasis. The effects of chronic administration of SHR3824 on peripheral insulin sensitivity and pancreatic β-cell function were also investigated.

Methods: The in vitro potency and selectivity of SHR3824 were assessed in HEK293 cells transfected with human SGLT2 or SGLT1. Acute and multi-dose studies were performed on ICR mice, GK rats and db/db mice to assess the ability of SHR3824 to enhance urinary glucose excretion and improve blood glucose levels. 2-Deoxyglucose uptake and insulin immunohistochemical staining were performed in the soleus muscle and pancreas, respectively, of db/db mice. A selective SGLT2 inhibitor BMS512148 (dapagliflozin) was taken as positive control.

Results: SHR3824 potently inhibited human SGLT2 in vitro, but exerted much weak inhibition on human SGLT1 (the IC50 values of SHR3824 against human SGLT2 and SGLT1 were 2.38 and 4324 nmol/L, respectively). Acute oral administration of SHR3824 (0.3, 1.0, 3.0 mg/kg) dose-dependently improved glucose tolerance in ICR mice, and reduced hyperglycemia by increasing urinary glucose excretion in GK rats and db/db mice. Chronic oral administration of SHR3824 (0.3, 1.0, 3.0 mg·kg(-1)·d(-1)) dose-dependently reduced blood glucose and HbA1c levels in GK rats and db/db mice, and significantly increased insulin-stimulated glucose uptake in the soleus muscles and enhanced insulin staining in the islet cells of db/db mice.

Conclusion: SHR3824 is a potent and selective SGLT2 inhibitor and exhibits antidiabetic efficacy in several rodent models, suggesting its potential as a new therapeutic agent for the treatment of type 2 diabetes.

Show MeSH
Related in: MedlinePlus