Quinoline-Based Neuropilin-1 Antagonists Exhibit a Pure Antagonist Profile and Block Vascular Endothelial Growth Factor-Induced Pain

Nociceptive pain, resulting from tissue injury or inflammation, affects a large portion of the global population. This type of pain is commonly treated by small molecules that are associated with a variety of drawbacks, including addiction and potential liver or kidney damage, highlighting the need for new therapeutic strategies. Here, we report the design, synthesis, and characterization of EG01449 (<b>12h</b>), a quinoline-based neuropilin-1 (NRP1) antagonist with analgesic effects in vascular endothelial growth factor (VEGF)-induced pain models. Neuropilin-1 is a critical coreceptor mediating VEGF signaling. In models of VEGF-induced pain, the VEGFA₁₆₅a isoform increases currents through voltage-gated sodium and calcium channels in dorsal root ganglia sensory neurons. Notably, this effect was mitigated upon the inhibition of NRP1 by <b>12h,</b> while <b>12h</b> alone showed no discernible impact on sodium currents. Compound <b>12h</b> also attenuated sensitivity to mechanical stimuli and cold-induced allodynia. Unlike the previously reported NRP1-targeting compounds that may activate intracellular signaling, <b>12h</b> did not activate p38 mitogen-activated protein kinase and exhibited a purely inhibitory pharmacological profile. Structural comparison using X-ray crystallography revealed an additional hydrogen bond that contributes to the increased stabilization of the <b>12h</b>/NRP1 complex. These findings demonstrate that the NRP1 inhibitor <b>12h</b> elicits an antinociceptive effect and highlight the impact of subtle structural modifications on biological outcomes. NRP1 antagonism thus represents a promising new modality for the treatment of chronic pain conditions.