Flupirtine Analogue Synthesis and Screening for the Treatment of Chemotherapy-Induced Neuropathic Pain

PROJECT SUMMARY Chemotherapy-induced neuropathic pain (CINP) is a common side effect for cancer patients and can greatly reduce patients’ quality of life. Although a wide range of pharmacological agents have been investigated in clinical trials as potential CINP therapies, currently approved analgesics for neuropathic pain are inadequate and offer limited beneficial effects in ameliorating CINP. Flupirtine, a non-opioid and non-steroidal anti- inflammatory drug analgesic, can effectively relieve various pain conditions in clinical studies. However, safety concerns, particularly rare but severe liver toxicity, led to restrictions on its use and eventual withdrawal from the market in the U.S. The adverse side effects of flupirtine that induce hepatotoxicity have been shown to not be linked with the primary antinociceptive mechanism of action. We have developed a flupirtine analogue library and demonstrated that one of the compounds (compound 5) had a much faster metabolism rate than the flupirtine parent and did not induce hepatotoxicity after intraperitoneal injection. We have also successfully developed both short-term and long-term mouse CINP models. Our results showed that compound 5 effectively ameliorated short-term CINP, as evidenced by various pain behavior tests. In this proposal, we will further synthesize and screen flupirtine analogues through structural modification to enhance their liver safety profile while maintaining or even improving therapeutic efficacy to effectively relieve CIPN. The specific aims of the studies are (1) to strategically develop potent Kv7.2/7.3 activators unable to form hepatotoxic metabolites, (2) to determine the analgesic efficacies of flupirtine analogues in the CINP mouse models. This proposal will develop a series of novel flupirtine analogues with reduced or eliminated hepatotoxicity as non-opioid analgesics to relieve CINP and treat various other pain conditions and non-pain-related diseases.