Abstract

Sodium-glucose cotransporter two (SGLT2) inhibitors are reapproved for heart condition (HF) medical aid in patients with and while not polygenic disorder. However, the initial glucose-lowering indication of SGLT2i has obstructed their uses in vas clinical follow. A challenge of SGLT2i then becomes the way to separate their anti- HF activity from glucose-lowering side-effect. to deal with this issue, we have a tendency to conducted structural repurposing of EMPA, a representative SGLT2 matter, to strengthen anti-HF activity and cut back the SGLT2- inhibitory activity consistent with structural basis of inhibition of SGLT2. Compared to EMPA, the best by-product JX01, that was made by methylation of C2-OH of the aldohexose ring, exhibited weaker SGLT2-inhibitory activity (IC50 > a hundred nmol/L), and lower symptom and glucose-lowering side-effect, higher NHE1-inhibitory activity and cardioprotective impact in HF mice. Moreover, JX01 showed sensible safety profiles in respect of singledose/ repeat-dose toxicity and hERG activity, and sensible pharmacokinetic properties in each mouse and rat species. Jointly, this study provided a paradigm of drug repurposing to find novel anti-HF medication, and indirectly incontestable that SGLT2-independent molecular mechanisms play a crucial role in cardioprotective effects of SGLT2 inhibitors.