https://www.scienceopen.com/hosted-document?doi=10.15212/AMM-2023-0051
Announcing a new publication for
Acta Materia Medica journal. 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.
Prior research showed that thoughtful structural modifications can dissociate the anti-heart failure activity from glucose-lowering effects. Moreover, it was shown 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 this 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.
This 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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eISSN 2737-7946
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Xiao Li, Yue Yao and Luoyifan Zhou et al. Glyceraldehyde derivatives inspired by empagliflozin as potential anti-heart failure agents independent of glucose-lowering effects.
Acta Materia Medica. 2024. Vol. 3(2):133-146. DOI: 10.15212/AMM-2024-0009