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Sodium Channel Modulators

Sodium Channel Modulators

In addition to the T-type calcium channels being targeted for pain, Zalicus has been actively pursuing another class of Ion channel for pain drug discovery and therapeutic intervention. Voltage-gated Sodium channels (abbreviated NaV) crucially regulate pain signaling by mediating sodium ion currents that contribute to the excitability of both peripheral pain-sensing neurons and also neurons within the spinal cord that relay pain signals to the brain. Several distinct types of sodium channels are important for setting the threshold and influencing the frequency, sustainability and intensity of pain signaling.


Of the ten sodium channel genes found in humans, the Nav1.7 and Nav1.8 types are of particular interest related to multiple chronic pain conditions as they are validated in both humans and commonly used preclinical models. For example, in humans naturally occurring loss-of-function genetic mutations in the NaV1.7 channel lead to the complete abolition of pain sensation while other gain-of-function NaV1.7 mutations cause severe chronic pain syndromes. Further, in animal models it has been shown that the suppression of either NaV1.7 or NaV1.8 channels reduces various kinds of acute and neuropathic pain.


Addressing these attractive targets for pain intervention, Zalicus has utilized its considerable expertise in Ion channels to design, characterize and develop novel, orally available agents that modulate the physiological functioning of NaV1.7 and NaV1.8 channels. The goal is to specifically target the increased firing and hypersensitivity in peripheral and spinal cord neurons that express NaV1.7 and NaV1.8 and that are associated with chronic inflammatory and neuropathic pain.


Representing the considerable progress that Zalicus has made to date, a pipeline of preclinical agents shown to affect NaV1.7 and NaV1.8 channels has been generated and was being studied as part of our collaboration with Hydra Biosciences Inc. A number of these new compounds have been found to both reduce the excitability of neurons and to reverse pain hypersensitivity in animal models of acute and neuropathic pain. By targeting  sodium channels in the peripheral and central nociceptive signaling pathways through a unique mechanism of action Zalicus has the opportunity to develop novel classes of safe and effective pain therapeutics.


Zalicus believes that the targeting of selective sodium channels complements its existing T-type calcium channel pain program.