{"doi":"10.1016/j.apsb.2021.09.018","title":"Structure-guided discovery of potent and oral soluble epoxide hydrolase inhibitors for the treatment of neuropathic pain","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.","journal":"Acta Pharmaceutica Sinica B","year":2021,"id":180623,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":17,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9477,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2021-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":730673,"name":"Ruolin Cao","orcid":null,"position":1,"is_corresponding":false},{"id":479645,"name":"Lu Chen","orcid":"0000-0002-8097-2699","position":2,"is_corresponding":false},{"id":729972,"name":"Jian‐Wen Sun","orcid":"0000-0002-8384-553X","position":3,"is_corresponding":false},{"id":730674,"name":"Yajie Shi","orcid":null,"position":4,"is_corresponding":false},{"id":729973,"name":"Yang Fu","orcid":"0000-0002-5068-7248","position":5,"is_corresponding":false},{"id":242185,"name":"Bruce D. Hammock","orcid":"0000-0003-1408-8317","position":6,"is_corresponding":false},{"id":730675,"name":"Zhonghui Zheng","orcid":null,"position":7,"is_corresponding":false},{"id":719091,"name":"Zhongbo Liu","orcid":"0000-0003-0075-1261","position":8,"is_corresponding":false},{"id":719092,"name":"Guoliang Chen","orcid":"0000-0003-3674-5226","position":9,"is_corresponding":false},{"id":719083,"name":"Fangyu Du","orcid":"0000-0001-7975-7775","position":0,"is_corresponding":true}],"reference_count":34,"raw_metadata":null,"created_at":"2026-07-18T23:47:57.268805Z","pmid":"35530144","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}