JNJ-63533054

JNJ-63533054 is a potent, selective and orally active GPR139 agonist with an EC₅₀ of 16 nM for human GPR139 (hGPR139). JNJ-63533054 shows selective for GPR139 over other GPCRs, ion channels, and transporters. JNJ-63533054 can cross the blood-brain barrier (BBB)^[1][2]. IC50 & Target: EC50: 16 nM (Human GPR139), 63 nM (Rat GPR139) and 28 nM (Mouse GPR139)^[1] In Vitro: JNJ-63533054 specifically activates human GPR139 in the calcium mobilization (EC₅₀ of 16 nM) and GTPγS binding (EC₅₀ of 17 nM) assays. JNJ-63533054 also activates the rat and mouse GPR139 receptor with similar potency (rat EC₅₀ of 63 nM, mouse EC₅₀ of 28 nM)^[1].
In a saturation study for human GPR139, a single population of high-affinity binding sites for [3H] JNJ-63533054 is observed (K_d of 10 nM). The B_max value is 26 pmol/mg of protein. Saturation studies for the rat GPR139 and mouse GPR139 yielded K_d values within the same range (32 nM and 23 nM, respectively; B_max = 8.5 pmol/mg of protein and 6.2 pmol/mg of protein, respectively)^[1]. In Vivo: JNJ-63533054 (3-30 mg/kg; oral administration; once; SD rats) treatment induces a dose-dependent reduction in locomotor activity in the first hour^[1].
The pharmacokinetics of JNJ-63533054 (Compound 7c; 1 mg/kg iv; 5 mg/kg po) in rat is examined. The IV clearance is 53 mL/min/kg, the C_max is 317 ng/mL (~1 μM), the t_1/2 is 2.5 hours, and JNJ-63533054 is able to cross the blood-brain barrier (BBB) with a brain to plasma ratio (b/p) of 1.2^[2].