c-jun-N-Terminal Kinase (JNK) for the Treatment of Amyotrophic Lateral Sclerosis
Final rept. 30 Sep 2012-29 Dec 2014
SCRIPPS RESEARCH INST LA JOLLA CA
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250 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. Moreover, two additional classes of JNK inhibitors have also been generated as backups. 80 compounds from the pyridopyrimidinone class have been synthesized and tested in biochemical and cell based assays, and approximately 25 compounds from the amino acid transporter analog class have been made and tested in biochemical assays. 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 mM. SR-11935, a highly selective JNK23 isoform inhibitor from the aminopyrazoles class has been optimized for potency, selectivity, pharmacokinetics, and brain penetration and has been tested in vitro to see if it protects motor neurons from Tg SOD1 G93A mice from astrocyte-mediated toxicity. SR-11935 demonstrated near 100 protection of motor neurons from astrocytemediated toxicity at 50 nM indicating the high potency and in vitro efficacy of this JNK23 isoform selective inhibitor. In addition, SR-3306 and SR-11935 have been tested for efficacy in vivo in transgenic G93A SOD1 mice. Preliminary results show that SR-3306 and SR-11935, an aminopyrimidine and aminopyrazole, respectively, are well tolerated with no adverse effects after once daily dosing for 90 days at 30 mgkg, and 40 mgkg, respectively.
- Medicine and Medical Research