JNJ-26489112, a Voltage-gated Na+ and N-type Ca2+ Channels Inhibitor

JNJ-26489112, a Voltage-gated Na⁺ and N-type Ca²⁺ Channels Inhibitor

By Edward Jenner 2021-04-22 #Anticonvulsant, #CA-II, #Ca2+, #K+, #Na+

Anticonvulsants are a diverse group of pharmacological agents used in the treatment of epileptic seizures. Broad-spectrum anticonvulsants are of considerable interest as antiepileptic drugs. In this study, researchers identified promising JNJ-26489112. In particular, JNJ-26489112 exhibits excellent anticonvulsant activity in rodents against audiogenic, electrically-induced, and chemically-induced seizures.

Anticonvulsants suppress the excessive rapid firing of neurons during seizures. Anticonvulsants also prevent the spread of the seizure within the brain. JNJ-26489112 acts as a broad-spectrum anticonvulsant. Mechanistically, JNJ-26489112 inhibits voltage-gated Na⁺ channels and N-type Ca²⁺ channels, and was effective as a K⁺ channel opener.

Many anticonvulsant agents are potent inducers of liver enzymes. The anticonvulsant profile of JNJ-26489112 suggests that it may be useful for treating multiple forms of epilepsy, including refractory epilepsy, with a favorable margin of safety. JNJ-26489112 is a very weak inhibitor of CA-II, with an IC₅₀ value of 35 μM (K_i=8.8 μM) in the CO₂ hydration assay. In addition, JNJ-26489112 is also a weak inhibitor of CA-I (IC₅₀=18 μM; K_i=2.2 μM).

JNJ-26489112 exhibits excellent broad-spectrum anticonvulsant activity in rodents against audiogenic, electrically-induced, and chemically-induced seizures, with very weak inhibition of human CA-II (IC₅₀=35 μM). Consequently, JNJ-26489112 exhibits good antiseizure activity in the antiepileptic model. Moreover, JNJ-26489112 inhibits Na⁺, kainate, and KCNQ2 channels to varying degrees. Thus, its action at several targets appears to be responsible for the observed neurostabilizing effects.

To summarise, JNJ-26489112 limits seizure spread and elevates seizure threshold in animal models. As a result, JNJ-26489112 has the potential to be effective in refractory, or pharmacoresistant, epilepsy.

Reference:
David F McComsey, et al. Novel, broad-spectrum anticonvulsants containing a sulfamide group: pharmacological properties of (S)-N-[(6-chloro-2,3-dihydrobenzo[1,4]dioxin-2-yl)methyl]sulfamide (JNJ-26489112). J Med Chem. 2013 Nov 27;56(22):9019-30.