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

Fangyu DU; Ruolin Cao; Lu Chen; Jianwen Sun; Yajie Shi; Yang FU; Bruce D Hammock; Zhonghui Zheng; Zhongbo Liu; Guoliang Chen

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

Author: Fangyu DU ¹ ; Ruolin CAO ¹ ; Lu CHEN ¹ ; Jianwen SUN ¹ ; Yajie SHI ¹ ; Yang FU ¹ ; Bruce D HAMMOCK ² ; Zhonghui ZHENG ³ ; Zhongbo LIU ⁴ ; Guoliang CHEN ¹
Author Information

1. Key Laboratory of Structure-Based Drug Design & Discovery of Ministry of Education, School of Pharmaceutical Engineering, Shenyang Pharmaceutical University, Shenyang 110016, China.
2. Department of Entomology and Nematology and UC Davis Comprehensive Cancer Center, University of California Davis, Davis, CA 95616, USA.
3. Shandong Xinhua Pharmaceutical Co., Ltd., Zibo 255086, China.
4. School of Pharmacy, Shenyang Pharmaceutical University, Shenyang 110016, China.
Publication Type:Journal Article
Keywords: Analgesia; Inhibitor; Neuropathic pain; Soluble epoxide hydrolase; Synthesis
From: Acta Pharmaceutica Sinica B 2022;12(3):1377-1389
CountryChina
Language:English
Abstract: 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 4 as lead compound. A preferential modification of piperidinyl to 3-carbamoyl piperidinyl was identified for this series via structure-based rational drug design. Compound A20 exhibited moderate percentage plasma protein binding (88.6%) and better metabolic stability in vitro. After oral administration, the bioavailability of A20 was 28.6%. Acute toxicity test showed that A20 was well tolerated and there was no adverse event encountered at dose of 6.0 g/kg. Inhibitor A20 also displayed robust analgesic effect in vivo 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 A20 significantly alleviated pain and improved the health status of the rats, demonstrating that A20 was a promising candidate to be further evaluated for the treatment of neuropathic pain.