Structural repurposing of SGLT2 inhibitor empagliflozin for strengthening anti-heart failure activity with lower glycosuria

Xu, Yixiang; Zhang, Chao; Jiang, Kai; Yang, Xinchun; Chen, Feng; Cheng, Zhiyang; Zhao, Jianlin; Jia-xing, Cheng; Li, Xiaokang; Chen, Xin; Zhou, Luoyifan; Hao, Dejun; Huang, Yunyuan; Xiang, Yaozu; Li, Jian

doi:10.1016/j.apsb.2022.08.023

Cited by 6 publications

(4 citation statements)

References 31 publications

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“…Of note was the moderate impact of EMPA on improving exercise tolerance, whereas compound 12 demonstrated a significant enhancement in exercise tolerance. Mechanistic studies indicated that compound 12 inhibited the activity of NHE1 in a dose-dependent fashion, which is consistent with the findings of a previous study [18]. In addition, compound 12 exhibited good pharmacokinetic and safety profiles.…”

Section: Introductionsupporting

confidence: 89%

“…Our previous work has shown that the cardioprotective effects of EMPA partly stems from the inhibition of sodium hydrogen exchanger 1 (NHE1) on the myocardial membrane [17]. A corollary study showed that rational structural repurposing of EMPA dissociates anti-HF activity from glucose-lowering effects [18], and supports an SGLT2independent molecular mechanism as the key role for the cardioprotective effects of SGLT2 inhibitors. The subtle modification of the glucose ring, an SGLT2 inhibitor pharmacophore for sustaining SGLT2 inhibitory activity, in EMPA generated the candidate JX01, which exhibits a superior cardioprotective effect with reduced glycosuria and fewer glucose-lowering side effects to EMPA.…”

Section: Introductionmentioning

confidence: 97%

“…Scaffold hopping is an effective strategy for obtaining novel lead compounds [19]. During modification of the EMPA glucose ring, we obtained a new compound, JX22, by replacing the glucose ring with glyceraldehyde [18]. JX22 exhibits superior cardiomyocyte protective effects compared to EMPA, albeit with a notable increase in cytotoxicity.…”

Section: Introductionmentioning

confidence: 99%

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Glyceraldehyde derivatives inspired by empagliflozin as potential anti-heart failure agents independent of glucose-lowering effects

Li,

Yao,

Zhou

et al. 2024

Acta Materia Medica

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Sodium-glucose cotransporter 2 inhibitors are a class of glucose-lowering drugs known for robust cardiovascular protective properties. However, the side effects induced by Sodium-glucose cotransporter 2 inhibition limit application in cardiovascular medicine. Our prior research showed that thoughtful structural modifications can dissociate the anti-heart failure activity from glucose-lowering effects. Moreover, we showed that the glyceraldehyde derivative, JX22, developed by scaffold hopping from empagliflozin, exhibits a superior cardiomyocyte protective effect, albeit with increased cytotoxicity compared to empagliflozin. In the current study systematic structural modifications of JX22 were performed to enhance anti-heart failure efficacy and safety, while reducing glucose-lowering activity. Twenty glyceraldehyde-based derivatives were synthesized and compound 12 emerged as an optimal candidate by exhibiting an improved cytoprotective effect compared to JX22. Compound 12 significantly inhibited the activity of NHE1 on the myocardial membrane, thereby maintaining intracellular ion homeostasis. In vivo efficacy results demonstrated that compound 12 at 10 mg/kg significantly ameliorated cardiac dysfunction, myocardial fibrosis, and exercise tolerance in isoproterenol-induced heart failure mice without a glucose-lowering effect. Furthermore, compound 12 exhibited favorable safety profiles in single-dose toxicity and hERG inhibition tests, along with promising pharmacokinetic properties in mice. The current study not only underscores the potential of compound 12 for further investigation but also highlights the effectiveness of the scaffold hopping strategy.

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Section: Introductionsupporting

confidence: 89%

Section: Introductionmentioning

confidence: 97%

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Glyceraldehyde derivatives inspired by empagliflozin as potential anti-heart failure agents independent of glucose-lowering effects

Li,

Yao,

Zhou

et al. 2024

Acta Materia Medica

Self Cite

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“…In addition to glucose-lowering effects, SGLT2 inhibitor has also been shown to have significant cardiovascular protective effects ( 16 – 19 ). The main manifestations are reducing blood pressure, regulating cardiac energy metabolism ( 16 ), improving vascular function ( 15 , 20 ), inhibiting the sympathetic nervous system ( 21 , 22 ), and preventing adverse myocardial remodeling ( 23 ). In addition, there is growing evidence that the use of selected SGLT2 inhibitors in patients with atherosclerotic cardiovascular disease (ASCVD) can improve cardiovascular outcomes ( 24 ).…”

Section: Introductionmentioning

confidence: 99%

SGLT2 inhibitor improves the prognosis of patients with coronary heart disease and prevents in-stent restenosis

Zhang,

Deng,

et al. 2024

Front. Cardiovasc. Med.

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Coronary heart disease is a narrowing or obstruction of the vascular cavity caused by atherosclerosis of the coronary arteries, which leads to myocardial ischemia and hypoxia. At present, percutaneous coronary intervention (PCI) is an effective treatment for coronary atherosclerotic heart disease. Restenosis is the main limiting factor of the long-term success of PCI, and it is also a difficult problem in the field of intervention. Sodium-glucose cotransporter 2 (SGLT2) inhibitor is a new oral glucose-lowering agent used in the treatment of diabetes in recent years. Recent studies have shown that SGLT2 inhibitors can effectively improve the prognosis of patients after PCI and reduce the occurrence of restenosis. This review provides an overview of the clinical studies and mechanisms of SGLT2 inhibitors in the prevention of restenosis, providing a new option for improving the clinical prognosis of patients after PCI.

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A Senomorphlytic Three‐Drug Combination Discovered in Salsola collina for Delaying Aging Phenotypes and Extending Healthspan

Wang,

Liu,

Huang

et al. 2024

Advanced Science

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The pursuit of pharmacological interventions in aging aims focuses on maximizing safety and efficacy, prompting an exploration of natural products endowed with inherent medicinal properties. Subsequently, this work establishes a unique library of plant extracts sourced from Yunnan Province, China. Screening of this herbal library herein revealed that Salsola collina (JM10001) notably enhances both lifespan and healthspan in C. elegans. Further analysis via network pharmacology indicates that the p53 signaling pathway plays a crucial role in mediating the anti‐aging effects of JM10001. Additionally, this work identifies that a composition, designated as JM10101 and comprising three chemical constituents of JM10001, preserves the original lifespan‐extending activity in C. elegans. Both JM10001 and JM10101 mitigate aging symptoms in senescence‐accelerated mice treated with doxorubicin and in naturally aged mice. Notably, JM10101 exhibits a more sophisticated senomorphlytic role encompassing both senomorphic and senolytic functions than JM10001 in the modulation of senescent cells, offering a promising strategy for the discovery of combination drugs in the rational development of anti‐aging therapies.

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Structural repurposing of SGLT2 inhibitor empagliflozin for strengthening anti-heart failure activity with lower glycosuria

Cited by 6 publications

References 31 publications

Glyceraldehyde derivatives inspired by empagliflozin as potential anti-heart failure agents independent of glucose-lowering effects

Glyceraldehyde derivatives inspired by empagliflozin as potential anti-heart failure agents independent of glucose-lowering effects

SGLT2 inhibitor improves the prognosis of patients with coronary heart disease and prevents in-stent restenosis

A Senomorphlytic Three‐Drug Combination Discovered in Salsola collina for Delaying Aging Phenotypes and Extending Healthspan

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