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Hydrolytic Activity of Mitochondrial F1FO-ATP Synthase as a Target for Myocardial Ischemia-Reperfusion Injury: Discovery and In Vitro and In Vivo Evaluation of Novel Inhibitors
Ist Teil von
Journal of medicinal chemistry, 2023-11, Vol.66 (22), p.15115-15140
Erscheinungsjahr
2023
Quelle
Alma/SFX Local Collection
Beschreibungen/Notizen
F1FO-ATP synthase is the mitochondrial complex responsible for ATP production. During myocardial ischemia, it reverses its activity, hydrolyzing ATP and leading to energetic deficit and cardiac injury. We aimed to discover novel inhibitors of ATP hydrolysis, accessing the druggability of the target within ischemia(I)/reperfusion(R) injury. New molecular scaffolds were revealed using ligand-based virtual screening methods. Fifty-five compounds were tested on isolated murine heart mitochondria and H9c2 cells for their inhibitory activity. A pyrazolo[3,4-c]pyridine hit structure was identified and optimized in a hit-to-lead process synthesizing nine novel derivatives. Three derivatives significantly inhibited ATP hydrolysis in vitro, while in vivo, they reduced myocardial infarct size (IS). The novel compound 31 was the most effective in reducing IS, validating that inhibition of F1FO-ATP hydrolytic activity can serve as a target for cardioprotection during ischemia. Further examination of signaling pathways revealed that the cardioprotection mechanism is related to the increased ATP content in the ischemic myocardium and increased phosphorylation of PKA and phospholamban, leading to the reduction of apoptosis.
Sprache
Englisch
Identifikatoren
eISSN: 1520-4804
DOI: 10.1021/acs.jmedchem.3c01048
Titel-ID: cdi_proquest_miscellaneous_2888034549
Format
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