Discovery and development of modulators of ion channels for the topical treatment of neuropathic pain

Neuropathic pain, caused by nervous system dysfunction, leads to chronic pain due to abnormal sensory neuron excitability. Two key channels in pain transmission, TRPV1 and NaV1.7, are crucial therapeutic targets. While TRPV1 antagonists face clinical setbacks due to adverse effects like hyperthermia, NaV1.7 blockers struggle with selectivity and safety due to high similarity among NaV channels, especially in the heart. This work aims to develop safer topical treatments for peripheral neuropathic pain using two strategies: the soft drug concept and PROTAC technology. For TRPV1, we combined these approaches to create soft PROTACs, aiming for improved safety and efficacy. Building on prior medicinal chemistry efforts, we identified two TRPV1 antagonists as warheads for different soft PROTAC designs. To introduce a metabolic “soft spot,” we employed the Passerini three-component reaction (MCR) for its efficiency in generating diverse compounds. Since PROTACs typically degrade cytosolic proteins, targeting the transmembrane TRPV1 presents a challenge. Additionally, to modulate the endovanilloid/endocannabinoid system, we developed dual TRPV1/CB inhibitors using the Passerini MCR. By combining endogenous TRPV1/CB modulators as “head” groups with fatty acids as “tails,” we created a new class of dual-acting compounds with potential for pain management. For NaV1.7, we designed three compound series based on literature-reported selective inhibitors: acylsulfonamides, biaryls, and soft lacosamide analogues—a neuropathic pain drug currently in trials. These were synthesized using both Passerini MCR and traditional methods. This work introduces innovative soft drug and PROTAC strategies for neuropathic pain, while advancing soft analogues of existing drugs, with broader applications in pain management.