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ID: ALA2434828
Journal: Bioorg Med Chem Lett
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.
Authors: Kato Y, Fuchi N, Saburi H, Nishimura Y, Watanabe A, Yagi M, Nakadera Y, Higashi E, Yamada M, Aoki T.
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.
CiteXplore: 24035338