JNJ-55308942

JNJ-55308942 is a high-affinity, selective, brain-penetrant P2X7 functional antagonist (hP2X7: IC₅₀=10 nM, K_i=7.1 nM; rP2X7: IC₅₀=15 nM, K_i=2.9 nM). JNJ-55308942 is orally bioavailable, binds to brain P2X7 and blocks IL-1β release from adult rodent brain^[1][2]. In Vitro: JNJ-55308942 shows pK_is of 8.1and 8.5 for recombinant human and rat P2X7 channels, respectively. In human blood and in mouse blood and microglia, JNJ-55308942 attenuates IL-1β release in a potent and concentration-dependent manner^[2]. In Vivo: JNJ-55308942 (30 mg/kg; p.o.) attenuates LPS-induced microglial activation in mice^[2].
In a model of Bacillus Calmette-Guerin (BCG)-induced depression, JNJ-55308942 dosed orally (30 mg/kg), reversed the BCG-induced deficits of sucrose preference and social interaction. After oral dosing, the compound exhibited both dose and concentration-dependent occupancy of rat brain P2X7 with an ED₅₀ of 0.07 mg/kg. The P2X7 antagonist (3 mg/kg, oral) blocked Bz-ATP-induced brain IL-1β release in conscious rats, demonstrating functional effects of target engagement in the brain^[2].
JNJ-55308942 (5 mg/kg; p.o.) shows the F, V_ss, CL, C_max and AUC_24h values are 81%, 1.7 L/kg, 3.7 mL min/kg, 1747 ng/mL, and 17549 (ng/mL) h, respectively^[1].