JNJ-26489112

Currently information is available for 20 potential anti-seizure drugs in clinical development. They include candidates with mechanisms of action similar to those of marketed AEDs (allopregnanolone, brivaracetam, ganaxolone, ICA-105665, NS1209, selurampanel); those with new mechanisms of action (beprodon, VX-765); compounds repurposed for the treatment of epilepsy (biperiden, bumetanide, fenfluramine, melatonin, nalutozan, pitolisant, quinidine, valnoctamide, verapamil); and finally candidates with currently unknown mechanisms of action (JNJ-26489112, UCB0942, YKP3089 (Cenobamate). Clinical development of anti-seizure drugs is still active but unexciting. Potential anti-seizure drugs continue to be largely identified by their activity against seizures provoked by electrical or chemical procedures in animals with normal brains. As in the past, this may lead to new drugs whose efficacy is not better than that of those already on the market.

In this study, several novel sulfamides were synthesized and evaluated for their acetylcholine esterase (AChE) and human carbonic anhydrase I, and II isoenzymes (hCA I and II) inhibition profiles. Reductive amination of methoxyacetophenones was used for the synthesis of amines. Amines were converted to sulfamoylcarbamates with chlorosulfonyl isocyanate (CSI) in the presence of BnOH. Pd-C catalyzed hydrogenolysis of sulfamoylcarbamates afforded sulfamides. These novel compounds were good inhibitors of the cytosolic hCA I, and hCA II with Ki values in the range of 45.9±8.9-687.5±84.3 pM for hCA I, and 48.80±8.2-672.2±71.9pM for hCA II. The inhibitory effects of the synthesized novel compounds on AChE were also investigated. The Ki values of these compounds were in the range of 4.52±0.61-38.28±6.84pM for AChE. These results show that hCA I, II, and AChE were effectively inhibited by the novel sulfamoylcarbamates 17-21 and sulfamide derivatives 22-26. All investigated compounds were docked within the active sites of the corresponding enzymes revealing the reasons of the effective inhibitory activity.