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 (12h), 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 12h, while 12h alone showed no discernible impact on sodium currents.
Compound 12h also attenuated sensitivity to mechanical
stimuli and cold-induced allodynia. Unlike the previously reported
NRP1-targeting compounds that may activate intracellular signaling, 12h 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 12h/NRP1 complex. These findings demonstrate that the NRP1
inhibitor 12h 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.