Title : Three-dimensional rational approach to the discovery of potent substituted cyclopropyl urea soluble epoxide hydrolase inhibitors - Takai_2015_Bioorg.Med.Chem.Lett_25_1705 |
Author(s) : Takai K , Chiyo N , Nakajima T , Nariai T , Ishikawa C , Nakatani S , Ikeno A , Yamamoto S , Sone T |
Ref : Bioorganic & Medicinal Chemistry Lett , 25 :1705 , 2015 |
Abstract :
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). |
PubMedSearch : Takai_2015_Bioorg.Med.Chem.Lett_25_1705 |
PubMedID: 25800114 |
Gene_locus related to this paper: human-EPHX2 |
Inhibitor | CHEMBL3401634 CHEMBL3114611 |
Gene_locus | human-EPHX2 |
Family | Epoxide_hydrolase |
Structure | 4X6X 4X6Y |
Takai K, Chiyo N, Nakajima T, Nariai T, Ishikawa C, Nakatani S, Ikeno A, Yamamoto S, Sone T (2015)
Three-dimensional rational approach to the discovery of potent substituted cyclopropyl urea soluble epoxide hydrolase inhibitors
Bioorganic & Medicinal Chemistry Lett
25 :1705
Takai K, Chiyo N, Nakajima T, Nariai T, Ishikawa C, Nakatani S, Ikeno A, Yamamoto S, Sone T (2015)
Bioorganic & Medicinal Chemistry Lett
25 :1705