JNJ-28583113 (JNJ28583113) is a potent, selective, brain penetrant TRPM2 antagonist with IC50 of 126 nM (hTRPM2).
JNJ-28583113 shows similar potency against species chimpanzee and rat TRPM2 with IC50 of 100 and 25 nM, respectively.
JNJ-28583113 shows no significant (IC50>10 uM) reactivity towards PARP or PARG and a panel for multiple known kinases GPCRs and ion channels, nine other TRP channels with exception of TRPM5 (IC50<1 uM).
Blocking TRPM2 via JNJ-28583113 caused phosphorylation of GSK3α and β subunits in cell assays.
JNJ-28583113 also protected cells from oxidative stress induced cell death as well as morphological changes induced by non-cytotoxic concentrations of H2O2。
JNJ-28583113 blunted cytokine release in response to pro-inflammatory stimuli in microglia.
JNJ-28583113 was brain penetrant but not suitable for systemic dosing as it was rapidly metabolized in vivo, but the in-vitro pharmacology of JNJ-28583113 is the best in class.