Development of a TRPA Antagonist Opioid Sparing Analgesic for Chronic Pain

Chronic pain affects over million Americans While opioids are recognized as the most effective drugs for the relief of pain the US is now suffering from an epidemic of abuse addiction and accidental overdose deaths resulting from prescription opioids The goal of this proposal is develop a novel non opioid analgesic drug devoid of addiction and abuse liabilities and to define its opioid sparing effect The combination of the non opioid analgesic and opioid drug has the potential to lower opioid requirements reduce side effects and decrease tolerance and abuse liabilities while maximizing pain relief Transient receptor potential ankyrin TRPA is a critical ligand gated ion channel on nociceptor nerve fiber endings which is a validated target for novel analgesic drug for treating chronic pain TRPA antagonists act directly on nociceptive nerve fiber endings to block initiation of action potentials by proalgesic substances and also have the capacity to inhibit peripheral sensitization Algomedix has discovered and is developing a new orally delivered analgesic based on inhibition of the TRPA receptor channel In this proposal we will assess a TRPA antagonist opioid combination to determine if the combination synergistically enhances the analgesic efficacy of opioids and potentially limits the development of tolerance Initial studies will demonstrate that newly synthesized potent and selective Algomedix TRPA antagonists with improved in vitro ADMET properties have analgesic efficacy in spinal neuron ligation SNL and chronic constriction injury models of neuropathic pain as well as opioid sparing efficacy in these pain models The lead compound ALGX XA strongly inhibits chronic pain in multiple animal models which include the SNL and chemotherapy induced peripheral neuropathic pain without adverse behavioral effects We therefore selected ALGX XA for chemical optimization in our proposed Phase SBIR project for analgesic drug development program Utilizing the well characterized structure activity relationship for this series and metabolic identification data we will synthesize a focused set of derivatives that specifically modify the metabolic hot spot to achieve increased stability while retaining potency and other desirable drug like properties The top modified leads meeting our matrix of ADMET selection criteria will be advanced for pharmacokinetic pharmacodynamic testing After defining efficacy in chronic pain in vivo safety pharmacology and non GLP toxicology in species will be conducted The milestone for the end of Phase II is the production of a therapeutic and backup clinical candidate Completion of these studies will enable a go no go decision for final GLP IND enabling studies Our ultimate goal is to develop a novel therapeutic targeting the TRPA receptor channel to treat chronic pain alone and as an opioid sparing drug combination product Project Narrative While opioids are recognized as effective drugs for the relief of pain the US is now suffering from an epidemic of abuse addiction and accidental overdose deaths from prescription The goal of this proposal is develop a novel non opioid analgesic drug devoid of addiction and abuse liabilities and to define its opioid sparing effect This novel non opioid analgesic drug may also be combined with an opioid drug to lower opioid requirements side effects tolerance and abuse liabilities while maintaining maximal levels of pain relief Recent evidence indicates the transient receptor potential ankyrin A TRPA channel is one of the most important detectors and integrators for pain sensory nociceptors Algomedix has discovered a series of potent and selective peripherally restricted TRPA antagonists having efficacy in chronic pain models without adverse behavioral effects The focus of this proposal will be to synthesize improved TRPA antagonists suitable for once or twice per day dosing define their analgesic efficacy after single and repeat dosing and their opioid sparing efficacy in rat models of chronic pain In addition the potential for abuse liability general in vivo safety and non GLP toxicology studies will also be determined These studies will enable final IND enabling studies and transition the development of this novel non opioid analgesic drug and combination product to clinical trials