BTB06584 (Synonyms: BTB)

Ischaemia compromises mitochondrial respiration. Consequently, the mitochondrial 1Fo-ATP synthase reverses and plays as a proton-pumping ATPase, so maintaining the mitochondrial membrane potential (ΔΨm), while accelerating ATP depletion and cell death. BTB06584 is an IF1-dependent selective inhibitor of the mitochondrial F1Fo-ATPase.

In vitro: BTB inhibited F1Fo-ATPase activity with no effect on the mitochondrial membrane potential (ΔΨm) or O2 consumption. ATP consumption decreased via inhibition of respiration, and ischaemic cell death was reduced. BTB efficiency increased by IF1 overexpression and reduced by silencing this protein. In addition, BTB rescued defective haemoglobin synthesis in zebrafish pinotage (pnt) mutants in which expression of the Atpif1a gene is lost [1].

In vivo: The BTB-mediated protection was further tested in neurons. Primary cultured cortical neurons of mice were exposed to OGD, treated or not with BTB, followed by RX. The resulting cell death was significantly reduced by BTB, as scored by PI staining, compared with cells left untreated during OGD [1].

Clinical trials: Currenlty no clinical data are available.

Reference:
[1] Ivanes F, Faccenda D, Gatliff J, Ahmed AA, Cocco S, Cheng CH, Allan E, Russell C, Duchen MR, Campanella M.   The compound BTB06584 is an IF1-dependent selective inhibitor of the mitochondrial F1 Fo-ATPase. Br J Pharmacol. 2014;171(18):4193-206.