PMID- 33248848 OWN - NLM STAT- MEDLINE DCOM- 20210423 LR - 20210423 IS - 1768-3254 (Electronic) IS - 0223-5234 (Linking) VI - 212 DP - 2021 Feb 15 TI - Ligand-based optimization to identify novel 2-aminobenzo[d]thiazole derivatives as potent sEH inhibitors with anti-inflammatory effects. PG - 113028 LID - S0223-5234(20)31000-X [pii] LID - 10.1016/j.ejmech.2020.113028 [doi] AB - Inhibition of the soluble epoxide hydrolase (sEH) is a promising new therapeutic approach in the treatment of inflammation. Driven by the in-house database product lead 1, a hybridization strategy was utilized for the design of a series of novel benzo [d]thiazol derivatives. To our delight, D016, a byproduct of compound 9, was obtained with an extraordinarily low IC(50) value of 0.1 nM but poor physical and chemical properties. After removal of a non-essential urea moiety or replacement of the urea group by an amide group, compounds 15a, 17p, and 18d were identified as promising sEH inhibitors, and their molecular binding modes to sEH were constructed. Furthermore, compounds 15a and 18d exhibited more effective in vivo anti-inflammatory effect than t-AUCB in carrageenan-induced mouse paw edema. Compound 15a also showed moderate metabolic stability with a half-time of 34.7 min. Although 18d was unstable in rat liver microsomes, it might be a "prodrug". In conclusion, this study could provide valuable insights into discovery of new sEH inhibitors, and compounds 15a and 18d were worthy of further development as potential drug candidates to treat inflammation. CI - Copyright (c) 2020 Elsevier Masson SAS. All rights reserved. FAU - Han, Yufei AU - Han Y AD - Key Laboratory of Structure-Based Drug Design and Discovery, Ministry of Education, Shenyang Pharmaceutical University, 103 Wenhua RoadShenhe District, Shenyang, 110016, China. FAU - Huang, Desheng AU - Huang D AD - State Key Laboratory Breeding Base-Hebei Province Key Laboratory of Molecular Chemistry for Drug, Hebei University of Science and Technology, Shijiazhuang, China. FAU - Xu, Sicong AU - Xu S AD - Key Laboratory of Structure-Based Drug Design and Discovery, Ministry of Education, Shenyang Pharmaceutical University, 103 Wenhua RoadShenhe District, Shenyang, 110016, China. FAU - Li, Lingling AU - Li L AD - State Key Laboratory Breeding Base-Hebei Province Key Laboratory of Molecular Chemistry for Drug, Hebei University of Science and Technology, Shijiazhuang, China. FAU - Tian, Ye AU - Tian Y AD - Key Laboratory of Structure-Based Drug Design and Discovery, Ministry of Education, Shenyang Pharmaceutical University, 103 Wenhua RoadShenhe District, Shenyang, 110016, China. FAU - Li, Shuo AU - Li S AD - State Key Laboratory Breeding Base-Hebei Province Key Laboratory of Molecular Chemistry for Drug, Hebei University of Science and Technology, Shijiazhuang, China. FAU - Chen, Cong AU - Chen C AD - Key Laboratory of Structure-Based Drug Design and Discovery, Ministry of Education, Shenyang Pharmaceutical University, 103 Wenhua RoadShenhe District, Shenyang, 110016, China. FAU - Li, Yingxiu AU - Li Y AD - Key Laboratory of Structure-Based Drug Design and Discovery, Ministry of Education, Shenyang Pharmaceutical University, 103 Wenhua RoadShenhe District, Shenyang, 110016, China. FAU - Sun, Yanping AU - Sun Y AD - State Key Laboratory Breeding Base-Hebei Province Key Laboratory of Molecular Chemistry for Drug, Hebei University of Science and Technology, Shijiazhuang, China. FAU - Hou, Yunlei AU - Hou Y AD - Key Laboratory of Structure-Based Drug Design and Discovery, Ministry of Education, Shenyang Pharmaceutical University, 103 Wenhua RoadShenhe District, Shenyang, 110016, China. FAU - Sun, Yongjun AU - Sun Y AD - State Key Laboratory Breeding Base-Hebei Province Key Laboratory of Molecular Chemistry for Drug, Hebei University of Science and Technology, Shijiazhuang, China. FAU - Qin, Mingze AU - Qin M AD - Key Laboratory of Structure-Based Drug Design and Discovery, Ministry of Education, Shenyang Pharmaceutical University, 103 Wenhua RoadShenhe District, Shenyang, 110016, China; Chinese People's Liberation Army Logistics Support Force No.967 Hospital, Dalian 116021, PR China. FAU - Gong, Ping AU - Gong P AD - Key Laboratory of Structure-Based Drug Design and Discovery, Ministry of Education, Shenyang Pharmaceutical University, 103 Wenhua RoadShenhe District, Shenyang, 110016, China. FAU - Gao, Zibin AU - Gao Z AD - State Key Laboratory Breeding Base-Hebei Province Key Laboratory of Molecular Chemistry for Drug, Hebei University of Science and Technology, Shijiazhuang, China. Electronic address: zbgao74@163.com. FAU - Zhao, Yanfang AU - Zhao Y AD - Key Laboratory of Structure-Based Drug Design and Discovery, Ministry of Education, Shenyang Pharmaceutical University, 103 Wenhua RoadShenhe District, Shenyang, 110016, China. Electronic address: yanfangzhao@126.com. LA - eng PT - Journal Article DEP - 20201117 PL - France TA - Eur J Med Chem JT - European journal of medicinal chemistry JID - 0420510 RN - 0 (Anti-Inflammatory Agents, Non-Steroidal) RN - 0 (Benzothiazoles) RN - 0 (Enzyme Inhibitors) RN - 0 (Ligands) RN - 9000-07-1 (Carrageenan) RN - EC 3.3.2.- (Epoxide Hydrolases) RN - EC 3.3.2.10 (EPHX2 protein, human) SB - IM MH - Animals MH - Anti-Inflammatory Agents, Non-Steroidal/chemical synthesis/chemistry/*pharmacology MH - Benzothiazoles/chemical synthesis/chemistry/*pharmacology MH - Carrageenan MH - Cell Survival/drug effects MH - Dose-Response Relationship, Drug MH - Edema/chemically induced/*drug therapy MH - Enzyme Inhibitors/chemical synthesis/chemistry/*pharmacology MH - Epoxide Hydrolases/*antagonists & inhibitors/metabolism MH - Hep G2 Cells MH - Humans MH - Inflammation/chemically induced/*drug therapy MH - Ligands MH - Male MH - Mice MH - Mice, Inbred BALB C MH - Microsomes, Liver/chemistry/metabolism MH - Molecular Docking Simulation MH - Molecular Structure MH - Rats MH - Rats, Sprague-Dawley MH - Structure-Activity Relationship OTO - NOTNLM OT - 2-aminobenzo[d]thiazole OT - Anti-Inflammation OT - Structure-based design OT - sEH COIS- Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper. EDAT- 2020/11/30 06:00 MHDA- 2021/04/24 06:00 CRDT- 2020/11/29 20:26 PHST- 2020/10/06 00:00 [received] PHST- 2020/11/11 00:00 [revised] PHST- 2020/11/13 00:00 [accepted] PHST- 2020/11/30 06:00 [pubmed] PHST- 2021/04/24 06:00 [medline] PHST- 2020/11/29 20:26 [entrez] AID - S0223-5234(20)31000-X [pii] AID - 10.1016/j.ejmech.2020.113028 [doi] PST - ppublish SO - Eur J Med Chem. 2021 Feb 15;212:113028. doi: 10.1016/j.ejmech.2020.113028. Epub 2020 Nov 17.