Three-dimensional rational approach to the discovery of potent substituted cyclopropyl urea soluble epoxide hydrolase inhibitors
| Autor: | Tomoko Nakajima, Shogo Nakatani, Kentaro Takai, Setsuko Yamamoto, Naoki Chiyo, Tetsuro Nariai, Akihisa Ikeno, Chihiro Ishikawa, Toshihiko Sone |
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| Rok vydání: | 2015 |
| Předmět: |
Cyclopropanes
Epoxide hydrolase 2 Stereochemistry Clinical Biochemistry Pharmaceutical Science Molecular Dynamics Simulation Crystallography X-Ray Biochemistry Cyclopropane Catalysis Structure-Activity Relationship chemistry.chemical_compound Catalytic Domain Drug Discovery Hydrolase Ic50 values Animals Humans Urea Moiety Molecular Biology Epoxide Hydrolases chemistry.chemical_classification Binding Sites Organic Chemistry Rats Enzyme chemistry cardiovascular system Molecular Medicine Protein Binding |
| Zdroj: | Bioorganic & Medicinal Chemistry Letters. 25:1705-1708 |
| ISSN: | 0960-894X |
| DOI: | 10.1016/j.bmcl.2015.02.076 |
| Popis: | We have previously reported a series of cyclopropyl urea derivatives as potent orally available soluble epoxide hydrolase (sEH) inhibitors. Here, we designed and synthesized three substituted cyclopropane derivatives that occupy all available pockets of sEH catalytic domain. Compound 14 with a diphenyl substituted cyclopropyl moiety showed good sEH inhibitory activity. Co-crystal structure of this compound and human sEH hydrolase catalytic domain revealed enzyme pockets occupied by the phenoxypiperidine part and the diphenyl cyclopropyl moiety. Furthermore, investigation of the phenoxypiperidine part of compound 14 resulted in the discovery of compound 19, which showed potent sEH inhibitory activity (sub-nM sEH IC50 values). |
| Databáze: | OpenAIRE |
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