Selective Kv7.2/3 activators for the treatment of neuropathic pain

Project Summary The successful management of chronic pain is inadequate in many patients and has contributed to the abuse of and addiction to opioidsa continuing major public health crisis in the United States and worldwideThe development of non addictive pain therapeutics can help counter opioid addiction and benefit patientsincluding those who suffer from neuropathic painand in particular diabetic neuropathic painDNPOur project s goal is to develop a safeefficacious and non addictive small molecule drug that activates Kvvoltage gated potassium channels to address overactive neuronal activity in DNPThe first specific aim is discover Kvactivators that favor Kvisoforms altered in DNP and found in dorsal root ganglianamely the KvisoformsThrough iterative lead optimization studies on our novel series of Kvactivatorswe are targeting Kvactivation with selectivity over both Kvchannels and another off target of other KvactivatorsGABAA receptorsThis approach is expected to decrease off target side effects observed with the use of earlier non biased Kvactivators including urinary retentionmediated by Kvand somnolence and dizzinessmediated by enhancement of GABAA receptor functionThis phase also includes optimization of absorptiondistributionmetabolismexcretionand toxicity profiles and building correlations between in vitro activities to in vivo efficacies in a neuropathic rat DNP modelA second animal modelthe LLspinal nerve constriction modelwill also be used to test the ability of candidate compounds to generalize to other forms of neuropathic painThe second specific aim will be to further characterize two to four advanced compounds by assessing additional pharmacological properties including CYPinduction time dependent inhibition and in vitro safety selectivity panelsThe third aim is to select a candidate for study in non GLP toxicology and pharmacokinetic studies in rodent and non rodent speciesSpecific aims four and five involve completing the studies needed to prepare an Investigational New DrugINDapplicationThese studies include Chemical Manufacturing Controls activities such as formulation studies and Good Manufacturing Practices synthesis of drug candidate followed by cardiovascular and safety pharmacology studiesandday Good Lab Practices toxicology studies in two animal speciesThis screening paradigm is intended to establish a clinic readywell tolerated and widely effective product to treat neuropathic pain Project Narrative The management of pain is a growing challenge for health providers and patients with overmillion adults estimated as having neuropathic painleading to increased prescription of opioids contributing to the recent rise in opioid misuse and addictionThe unmet need for the treatment of neuropathic pain include products with greater response rateseffectiveness in multiple types of painconvenience in usereduced abuse and addiction riskactivity via novel mechanismsand the potential for safety and effectiveness in combination with established treatmentsThe goal of this program is to develop a non addictive selective Kvpotassium channel activator to treat neuropathic pain and alleviate the reliance on addictive opioidswith an initial focus on diabetic neuropathic pain