JNJ-55308942 is a highly potent, selective, brain-penetrant P2X7 antagonist with Ki of 1.0 and 6.5 nM for rat and human hP2X7.
JNJ-55308942 demonstrates no significant activity against a panel of related P2X receptors (P2X1, P2X2, P2X3, P2X2/3, and P2X4.
JNJ-55308942 also shows insignificant inhibition of nine CYP isoforms (IC50>15 uM).
JNJ-55308942 exhibits excellent P2X7 receptor occupancy in the hippocampus of rats with low ED50 of 0.07 mg/kg and unbound plasma EC50 of 12 ng/mL, suppresses brain IL-1β release in vivo in freely moving rats challenged with the P2X7 agonist Bz-ATP.
JNJ-55308942 possesses good tolerability margins in preclinical species, as well as an acceptable cardiovascular safety profile in vivo.
