c-jun-N-Terminal Kinase (JNK) for the Treatment of Amyotrophic Lateral Sclerosis

120 aminopyrazoles, a new class of c-jun-N-terminal kinase JNK inhibitors, have been synthesized and the biochemical IC50 has been determined for JNK3, JNK2, JNK1, and p38. In addition, these compounds have been tested in cell-based assays that monitor the inhibition of c-jun phosphorylation and some drug metabolism and pharmacokinetic DMPK properties have been measured. The goal of this work is to find JNK3 isoform selective inhibitors. Eight novel aminopyrazoles have been developed with JNK3 selectivity 20-fold, three novel compounds have been developed with JNK3 selectivity 50-fold, one novel compound has been developed with JNK3 selectivity 200-fold, and two compounds have cell-based IC50s 1 M. In addition, SR-3306 has been tested for efficacy in vivo in transgenic G93A SOD1 mice. Preliminary results show that SR-3306, an aminopyrimidine, is well tolerated with no adverse effects after once daily dosing at 30 mgkg. Four other aminopyrimidines have been synthesized and are ready for in vitro and in vivo testing to see if they protect motor neuron degeneration.