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Bioorg Med Chem Lett. 2013 Nov 1;23(21):5975-9. doi: 10.1016/j.bmcl.2013.08.054. Epub 2013 Aug 20.

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.

Author information

1
Toray Industries Inc., Pharmaceutical Research Laboratories, 6-10-1 Tebiro, Kamakura, Kanagawa 248-8555, Japan. Electronic address: Yuko_Kato@nts.toray.co.jp.

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.

KEYWORDS:

Hypertension; Mean blood pressure; Spirocyclic diamine; Spontaneously hypertensive rat; Urea; sEH inhibitor

PMID:
24035338
DOI:
10.1016/j.bmcl.2013.08.054
[Indexed for MEDLINE]
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