| Title : Discovery of 2,8-diazaspiro[4.5]decane-based trisubstituted urea derivatives as highly potent soluble epoxide hydrolase inhibitors and orally active drug candidates for treating hypertension - Kato_2013_Bioorg.Med.Chem.Lett_23_5975 |
| Author(s) : Kato Y , Fuchi N , Saburi H , Nishimura Y , Watanabe A , Yagi M , Nakadera Y , Higashi E , Yamada M , Aoki T |
| Ref : Bioorganic & Medicinal Chemistry Lett , 23 :5975 , 2013 |
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Abstract :
We identified 2,8-diazaspiro[4.5]decane-based trisubstituted urea derivatives as highly potent soluble epoxide hydrolase (sEH) inhibitors and orally active agents for treating hypertension. Docking studies using human and murine sEH X-ray crystal structures revealed steric hindrance around the side chain of Phe406 of murine sEH. The trifluoromethyl moiety (11) was replaced with a trifluoromethoxy moiety (12) to prevent steric clash, and improved murine sEH inhibitory activity was observed. The oral administration of 12, 20, and 37 at a dose of 30mg/kg reduced blood pressure in spontaneously hypertensive rat, but had little effect on blood pressure in normotensive rat. |
| PubMedSearch : Kato_2013_Bioorg.Med.Chem.Lett_23_5975 |
| PubMedID: 24035338 |
Kato Y, Fuchi N, Saburi H, Nishimura Y, Watanabe A, Yagi M, Nakadera Y, Higashi E, Yamada M, Aoki T (2013)
Discovery of 2,8-diazaspiro[4.5]decane-based trisubstituted urea derivatives as highly potent soluble epoxide hydrolase inhibitors and orally active drug candidates for treating hypertension
Bioorganic & Medicinal Chemistry Lett
23 :5975
Kato Y, Fuchi N, Saburi H, Nishimura Y, Watanabe A, Yagi M, Nakadera Y, Higashi E, Yamada M, Aoki T (2013)
Bioorganic & Medicinal Chemistry Lett
23 :5975