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

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 IC 50 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.

Henagliflozin monotherapy in patients with type 2 diabetes inadequately controlled on diet and exercise: A randomized, double‐blind, placebo‐controlled, phase 3 trial

“…Henagliflozin (SHR3824) is a novel, highly selective, oral inhibitor of SGLT2 12,13 . Our previous phase 2 trial (NCT02366351) showed that 12‐week treatment of henagliflozin monotherapy provided efficacious glycaemic control, reduced body weight and blood pressure, and was generally well tolerated in Chinese patients with T2D and inadequate glycaemic control with diet and exercise (data submitted for publication).…”

“…3,11 Henagliflozin (SHR3824) is a novel, highly selective, oral inhibitor of SGLT2. 12,13 Our previous phase 2 trial (NCT02366351) showed that 12-week treatment of henagliflozin monotherapy provided efficacious glycaemic control, reduced body weight and blood pressure, and was generally well tolerated in Chinese patients with T2D and inadequate glycaemic control with diet and exercise (data submitted for publication). Herein, we conducted a phase 3 trial to further evaluate the efficacy and safety of henagliflozin monotherapy in this population, with results from the 24-week placebo-controlled period and additional 28-week extension period reported.…”

Mechanistic evaluation of the inhibitory effect of four SGLT-2 inhibitors on SGLT 1 and SGLT 2 using physiologically based pharmacokinetic (PBPK) modeling approaches

“…Where S′ is the substrate concentration for determining IC50 values ( Mascitti et al, 2011 ; Grempler et al, 2012 ; Yan et al, 2014 ; Cefalo et al, 2019 ; Wang et al, 2019 ; Fediuk et al, 2020 ). Km’ is the Michaelis constant of SGLT.…”

“…Henagliflozin is a novel SGLT 2 inhibitor, which has a similar structure to ertugliflozin ( Wang et al, 2016 ), and both 5 mg and 10 mg are the doses authorized for clinical use in china. Henagliflozin has an 1818-fold higher SGLT 2 selectivity as compared to SGLT transporters ( Yan et al, 2014 ). Sotagliflozin was approved for treating both T1DM and T2DM in the EU, and 200 mg or 400 mg are the doses authorized for clinical use ( He et al, 2022 ).…”

Quantification of 3‐n‐butylphthalide in beagle plasma samples by supercritical fluid chromatography with triple quadruple mass spectrometry and its application to an oral bioavailability study

“…3‐ n ‐Butylphthalide (NBP) [(±)‐3‐butyl‐1(3 H )‐isobenzofuranone] was firstly isolated from Chinese herbs, including Apium graveolens , Ligusticum sinensis , and Liqusticum Chuanxiong Hort , and has also been obtained by chemical synthesis . NBP is currently used clinically as a preferred drug for the treatment of ischemic stroke by increasing regional cerebral blood flow and inhibiting the release of glutamate and 5‐hydroxytryptamine . In addition, recent research has demonstrated that NBP displays beneficial effects by attenuating amyloid‐induced cell death in neuronal cultures , improving cognitive deficits and preventing neuronal cell death after focal cerebral ischemia in mice , and protecting cardiomyocytes from ischemia/reperfusion‐induced apoptosis .…”