Structure-guided discovery of potent and oral soluble epoxide hydrolase inhibitors for the treatment of neuropathic pain.

Soluble epoxide hydrolase (sEH) is related to arachidonic acid cascade and is over-expressed in a variety of diseases, making sEH an attractive target for the treatment of pain as well as inflammatory-related diseases. A new series of memantyl urea derivatives as potent sEH inhibitors was obtained using our previous reported compound as lead compound. A preferential modification of piperidinyl to 3-carbamoyl piperidinyl was identified for this series structure-based rational drug design. Compound exhibited moderate percentage plasma protein binding (88.6%) and better metabolic stability . After oral administration, the bioavailability of was 28.6%. Acute toxicity test showed that was well tolerated and there was no adverse event encountered at dose of 6.0 g/kg. Inhibitor also displayed robust analgesic effect and dose-dependently attenuated neuropathic pain in rat model induced by spared nerve injury, which was better than gabapentin and sEH inhibitor (±)-EC-5026. In one word, the oral administration of significantly alleviated pain and improved the health status of the rats, demonstrating that was a promising candidate to be further evaluated for the treatment of neuropathic pain.