Phenyl-benzyl-ureas with pyridazinone motif: Potent soluble epoxide hydrolase inhibitors with enhanced pharmacokinetics and efficacy in a paclitaxel-induced neuropathic pain model

The severe pain linked to chemotherapy-induced peripheral neuropathy (CIPN) often becomes a critical factor limiting the effective dosage of life-saving chemotherapy treatments. This debilitating side effect not only hampers the effectiveness of Cancer therapy but also poses challenges due to the adverse effects of current treatment options for managing CIPN-related pain complications. Soluble Epoxide Hydrolase (sEH) inhibitors, which elevate endogenous epoxy-fatty acid levels, have been shown to mitigate CIPN-related pain in different rodent models. In our quest to develop potent sEH inhibitors, we developed novel benzyl phenyl urea derivatives incorporating a pyridazinone ring alongside the urea group as a secondary pharmacophore. These compounds demonstrated remarkable potency in inhibiting sEH, with IC₅₀ values ranging from 0.2 to 57 nM. Compound FP9 (IC₅₀ = 0.2 nM), the most potent in this series, exhibited enhanced metabolic stability, translating into significantly improved oral bioavailability (F = 78 %). It consistently relieved pain perception in mice with paclitaxel-induced peripheral neuropathy, achieving a significant and sustained effect compared to gabapentin. In addition, docking studies and molecular dynamics simulations with FP9 provided valuable insights into the binding interactions between the inhibitor and the sEH binding site, offering direction for further optimization of new analogs. These findings align with recent research that highlights the beneficial effects of sEH inhibitors in reducing pain thresholds associated with CIPN.

Chemotherapy; EET; Hydrolase; Paclitaxel; Pain; Pyridazinone; Urea.