2. Academic Validation
  3. Ligand-based optimization to identify novel 2-aminobenzo[d]thiazole derivatives as potent sEH inhibitors with anti-inflammatory effects

Ligand-based optimization to identify novel 2-aminobenzo[d]thiazole derivatives as potent sEH inhibitors with anti-inflammatory effects

  • Eur J Med Chem. 2021 Feb 15;212:113028. doi: 10.1016/j.ejmech.2020.113028.
Yufei Han 1,  Desheng Huang 2,  Sicong Xu 1,  Lingling Li 2,  Ye Tian 1,  Shuo Li 2,  Cong Chen 1,  Yingxiu Li 1,  Yanping Sun 2,  Yunlei Hou 1,  Yongjun Sun 2,  Mingze Qin 3,  Ping Gong 1,  Zibin Gao 4,  Yanfang Zhao 5
Affiliations

Affiliations

  • 1 Key Laboratory of Structure-Based Drug Design and Discovery, Ministry of Education, Shenyang Pharmaceutical University, 103 Wenhua RoadShenhe District, Shenyang, 110016, China.
  • 2 State Key Laboratory Breeding Base-Hebei Province Key Laboratory of Molecular Chemistry for Drug, Hebei University of Science and Technology, Shijiazhuang, China.
  • 3 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.
  • 4 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.
  • 5 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.
PMID: 33248848 DOI: 10.1016/j.ejmech.2020.113028
Abstract

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 IC50 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.

Keywords

2-aminobenzo[d]thiazole; Anti-Inflammation; Structure-based design; sEH.

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