Design, Synthesis And Activity Evaluation Of New Na_v1.8Inhibitor

Chronic pain have influenced people’s nomal life seriously. Clinical analgesic drugs have no abviously analgesia activity for treatment of chronic pain. Now, chronic analgesic drugs have poor selectivity and biological activity, which can easily caused resistance and addiction. Hence, It’s very important to develop chronic analgesia inhibitor with novel structure feature.Sodium channels (Navl.x) belong to an transmembrane proteins which insert into cell membrane and modulate the transportation of sodium ions. Nav1.8is a key ion channel for regulating the excitability and transduction of chronic pain and has been recognized as an important target for the development of chronic analgesics. In this dissertation, three series of new Nav1.8inhibitors with novel structures are designed and synthesized.Major work were shown as follow:1-. Based on compounds A-803467and pyrazine-based blocks, three series of imidazolidin-2-one(L1-L9) and amide derivatives of pyrimidin-2-amine(L10-L24) and furan-2-ylmethanamine(L25-L33) were designed and synthesized by applying fragment splicing, replacement nucleus, electron equivalent, and other design principles. The structures of all synthesized target compounds were characterized by1H-NMR and FAB-MS.2、The inhibitory effect of all the synthetic compounds on Nav1.8channel expressed on HEK293T were evaluated at the drug concentration of10μM using whole-cell patch-clamp. The results showed that imidazolidin-2-one compounds had no obviously inhibitory activity of sodium currents. However, the pyrimidin-2-amine amides and furan-2-ylmethanamine amides exhibited potent inhibitory activities of sodium currents, especially compounds L11and L26, which inhibitory ration were65%and91%, respectively.3、Based on the effects of substitution, position isomerism and Bio-isostere on inhibitory activities, the structure-activity relationship(SAR) of target compounds were discussed. The results indicate that the substitutional position of right and left aryl ring and amide types have significant effects on inhibitory activities. The compounds exhibited high block activities when it can form hydrogen bond with residue in soudium channels or the benzene ring is substituted by nitrogen heterocyclic. Extension of one carbon atom between the middle ring and amino group has little effect on inhibitory activities. The SAR analyses provide some clues for further design and synthesis of new Nav1.8inhibitors.