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

how to separate their anti-HF activity from glucose-lowering side-effect. To address this issue, we conducted structural repurposing of EMPA, a representative SGLT2 inhibitor, to strengthen anti-HF activity and reduce the SGLT2-inhibitory activity according to structural basis of inhibition of SGLT2. Compared to EMPA, the optimal derivative JX01, which was produced by methylation of C2-OH of the glucose ring, exhibited weaker SGLT2-inhibitory activity (IC50 > 100 nmol/L), and lower glycosuria and glucose-lowering side-effect, better NHE1-inhibitory activity and cardioprotective effect in HF mice. Furthermore, JX01 showed good safety profiles in respect of single-dose/repeat-dose toxicity and hERG activity, and good pharmacokinetic properties in both mouse and rat species. Collectively, the present study provided a paradigm of drug repurposing to discover novel anti-HF drugs, and indirectly demonstrated that SGLT2-independent molecular mechanisms play an important role in cardioprotective effects of SGLT2 inhibitors.

Automated summary

To address the issue of separating ant-heart failure (HF) activity from glucose-lowering side-effects, the researchers conducted structural repurposing of the SGLT2 inhibitor EMPA. The optimized derivative JX01 showed weaker SGLT2-inhibitory activity and lower glucose-lowering side-effects, but better NHE1-inhibitory activity and HF mice cardioprotective effect. Furthermore, JX01 demonstrated good safety profiles and pharmacokinetic properties. This study provides a paradigm for discovering novel anti-HF drugs and indirectly highlights the importance of SGLT2-independent molecular mechanisms in the cardioprotective effects of SGLT2 inhibitors.