Substituted Pyridines as Sodium Channel Blockers

Voltage-gated sodium channels are found in both the peripheral and the central nervous system and are the primary mechanism for generation of the rapid upstroke portion of the action potential of excitable cells. Proper function of these channels is critical to normal neuronal function, while aberrant channel function is associated with several medical conditions, including pain. It has been suggested that Nav1.7, a tetrodotoxin-sensitive channel that is preferentially expressed in peripheral sympathetic and sensory neurons, plays a key role in acute, inflammatory, and neuropathic pain. In addition, it has been demonstrated that a number of local anesthetics, such as lidocaine and bupivacaine, exert their biological effects by interfering with sodium ion influx, further suggesting a link between pain sensation and sodium channels. The present disclosure describes a series of substituted aminopyridines useful as NaV1.7 blockers for the treatment of pain. © 2012 American Chemical Society.