JOURNAL OF MEDICINAL CHEMISTRY
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2023
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IF 7.3
Guang-Jing Feng,Yang-Fan Guo,Yuming Tang,Min Li,Yufei Jia,Zhimeng Li,Shuangshuang Wang,Hongmei Liu,Yuzhou Wu,Hai Dong
In this study, we have investigated the potential of two classes of thioglucoside analogues of gliflozins as antidiabetic drugs, one with substitutions of S-atoms in meta-positions (similar to C-glucoside SGLT2 inhibitors, TAGs A, B, and C) and the other with substitutions of S-atoms in ortho-positions (similar to O-glucoside SGLT2 inhibitors, TAGs D, E, F, and G). These TAGs were confirmed to show good stability against β-glucosidase and to have no acute toxicity to cultured cells. Most importantly, TAGs D, E, F, and G all showed high inhibitory activity against SGLT2 (IC50: 2.0–5.9 nM) and thus have great potential to be developed as new gliflozin drugs. Compared with the synthesis of C-glucoside gliflozins, the synthesis of TAGs is simple, efficient, and associated with low costs, high yields, and very mild reaction conditions.
研究领域:
药理学
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药物化学
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生物化学
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产品关联
DOI
PubMed
高影响因子
MOLECULAR DIVERSITY
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2025
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IF 3.8
Qin Fei,Zeng Huicong,Zhou Li,Zhou Zhenhua,Mao Yongxin,Zeng Youyan,Guo Rongxiang,Chen Kaixian,Zhao Dongyu,Yao Weiwei,Zhang Bin,Zhou Qian,Li Bo
The sodium–glucose co-transporter 2 (SGLT2) plays an important role in mediating glucose reabsorption within the renal filtrate and regulating blood glucose levels, which makes it a well-known target for diabetes mellitus. A number of SGLT2 inhibitors (SGLT2i) have been established as important antidiabetic drugs, and research on new SGLT2i with high affinity is ongoing. Herein, 101 compounds were screened from a compound library (approximately 16,000 compounds) using a virtual screening workflow that integrated various docking programs, pharmacophore modeling, and druggability filter. To verify the results of virtual screening, we established a HK-2 cell model with d-glucose derivative 2-[N-(7-nitrobenz-2-oxa-1,3-diazol-4-yl) amino]-2-deoxy-d-glucose (2-NBDG) for measuring glucose uptake via SGLT2. 12 candidate compounds were selected and purchased for subsequent experimental validation. Among these, 3 non-glycoside compounds significantly inhibited the 2-NBDG uptake in a dose-dependent manner and their IC 50 values for SGLT2 were 71.43 μM, 72.66 μM, and 91.44 μM, respectively. Mechanism studies demonstrated that all 3 compounds significantly downregulated SGLT2 level and activated silent information regulator 1 (SIRT1) expression in high-glucose-induced cell injury models. These findings confirmed the ability of these compounds to bind to SGLT2 and also revealed their potential mechanisms in regulating oxidative stress and metabolism. Furthermore, molecular dynamics simulation indicated the high binding stability of SGLT2 and 3 compounds complexes during a 100-ns simulation period. In conclusion, our results identified 3 potential SGLT2i and preliminarily elucidated their mechanism of action, which lays the foundation for the development of novel and potent non-glycoside SGLT2i in future. Graphical
研究领域:
药理学
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药物化学
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分子生物学
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糖尿病研究
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转化医学
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计算机辅助药物设计
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产品关联
DOI
PubMed
高影响因子
BIOFACTORS
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2023
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IF 6
Zichen Gui,Jiawen Wang,Yue Zhang,Binbin Wan,Zhiqiang Ke,Zhanhong Ren,Xiaosong Yang,Min Lei,Xiying Guo,Xiufen Liu,Changhan Ouyang,Ninghua Wu,Qingjie Chen
Cognitive impairment is increasingly recognized as an important comorbidity of diabetes progression; however, the underlying molecular mechanism is unclear. Dapagliflozin, an inhibitor of sodium-glucose co-transporter 2 (SGLT2), has shown promising effects against diabetes in rodent experiments and human clinical assays. This study aimed to determine the underlying mechanism and examine the effect of dapagliflozin on diabetic cognitive impairment. To create an in vivo model of diabetic cognitive impairment, streptozotocin (STZ)-induced diabetic mice were used. Dapagliflozin was administered to mice for 8 weeks. The context fear condition and Morris water maze test was used to evaluate mice's behavioral change. Western blotting was used to evaluate protein expression. Hematoxylin and eosin (HE) and Nissl staining were applied to monitor morphological and structural changes. Congo red staining was performed to identify the formation of senile plaques. Mitochondria morphology was examined using a transmission electron microscope, and blood flow in the mouse cerebral cortex was measured using a laser Doppler imaging assay. Comparison to the diabetes mellitus (DM) group, the dapagliflozin group had lower glucose levels. Behavioral studies have shown that dapagliflozin can restore memory deficits in diabetic mice. The murky cell membrane edges and Nissl bodies more difficult to identify in the DM group were revealed by HE and Nissl staining, which were both improved by dapagliflozin treatment. Dapagliflozin inhibited the progression of Aβ generation and the reduced cerebral blood flow in the DM group was rescued. After dapagliflozin treatment, damaged mitochondria and lack of SGLT2 in the hippocampus and cortex of diabetic mice were repaired. Diabetes-induced cognitive dysfunction was attenuated by dapagliflozin and the effect was indirect rather than direct.
研究领域:
药理学
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神经科学
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糖尿病研究
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产品关联
DOI
PubMed
高影响因子
PHYSIOLOGY & BEHAVIOR
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2023
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IF 2.9
Bo Pang,Lu-Lu Zhang,Bin Li,Feng-Xian Sun,Zhi-Da Wang
An antidiabetic agent sodium glucose co-transporter 2 (SGLT2) inhibitor ertugliflozin has been revealed to bind to catalytic anionic site of acetylcholinesterase (AChE), which is considered to be associated with the cognitive decline in neurodegenerative diseases, such as Alzheimer's disease (AD). The aim of the present study was thus to probe the effect of ertugliflozin on AD. Intracerebroventricular injection of streptozotocin (STZ/i.c.v) (3 mg/kg) was done bilaterally in male Wistar rats at 7–8 weeks of age. Two treatment doses (5 mg/kg and 10 mg/kg) of ertugliflozin were given intragastrically to STZ/i.c.v-induced rats for 20 days daily for behavioral assessment. Biochemical estimations of cholinergic activity, neuronal apoptosis, mitochondrial function and synaptic plasticity were performed. Behavioral results with ertugliflozin treatment revealed attenuation of cognitive deficit. Ertugliflozin also inhibited hippocampal AChE activity, downregulated pro-apoptotic marker expression, as well as mitigated mitochondrial dysfunction and synaptic damage in STZ/i.c.v rats. Importantly, we found that the hyperphosphorylation of tau in the hippocampus of STZ/i.c.v rats was decreased after oral administration of ertugliflozin, which was accompanied by decreased Phospho.IRS-1 Ser307 /Total.IRS-1 ratio and increased Phospho.Akt Ser473 /Total.Akt and Phospho.GSK3β Ser9 /Total.GSK3β ratios. Our results indicated that treatment with ertugliflozin reversed AD pathology, which may be associated with inhibition of insulin signaling disruption-induced tau hyperphosphorylation.
研究领域:
神经科学
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药理学
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神经退行性疾病
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认知障碍
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产品关联
DOI
PubMed
高影响因子
Journal of the American Heart Association
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2022
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IF 6.106
Xin‐Lin Zhang,Ting‐Yu Wang,Zheng Chen,Hong‐Wei Wang,Yong Yin,Lian Wang,Yong Wang,Biao Xu,Wei Xu
BackgroundHeart failure with preserved ejection fraction (HFpEF) remains an increasing public health problem with substantial morbidity and mortality but with few effective treatments. A novel inflammatory mechanism has been proposed, but the inflammatory signals promoting the development of HFpEF remain greatly unknown.Methods and ResultsSerum of patients with HFpEF was collected for measurement of circulating neutrophils and markers of neutrophil extracellular traps (NETs). To induce HFpEF phenotype, male C57BL/6 mice underwent uninephrectomy, received a continuous infusion of d‐aldosterone for 4 weeks, and maintained on 1.0% sodium chloride drinking water. Heart tissues were harvested, immune cell types determined by flow cytometry, NETs formation by immunofluorescence, and western blotting. Differentiated neutrophils were cultured to investigate the effect of HMGB1 (high mobility group protein B1) and SGLT2 (sodium‐glucose cotransporter‐2) inhibitor on NETs formation in vitro. Circulating neutrophils and NETs markers are elevated in patients with HFpEF, as are cardiac neutrophils and NETs formation in HFpEF mice. NETs inhibition with deoxyribonuclease 1 in experimental HFpEF mice reduces heart macrophages infiltration and inflammation and ameliorates cardiac fibrosis and diastolic function. Damage‐associated molecular pattern HMGB1 expression is elevated in cardiac tissue of HFpEF mice, and HMGB1 inhibition reduces heart neutrophil infiltration and NETs formation and ameliorates diastolic function. Lastly, SGLT2 inhibitor empagliflozin down‐regulates heart HMGB1 expression, attenuates NETs formation and cardiac fibrosis, and improves diastolic function in HFpEF mice.ConclusionsNETs contribute to the pathogenesis of HFpEF, which can be ameliorated by HMGB1 inhibition and SGLT2 inhibitors. Thus, HMGB1 and NETs may represent novel therapeutic targets for the treatment of HFpEF.
研究领域:
心脏病学
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免疫学
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药理学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
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