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

• Published in: Bioorganic & medicinal chemistry letters Vol. 23; no. 21; pp. 5975 - 5979
• Main Authors: Kato, Yuko, Fuchi, Nobuhiro, Saburi, Hajime, Nishimura, Yutaka, Watanabe, Ayano, Yagi, Mai, Nakadera, Yasuhito, Higashi, Eriko, Yamada, Masateru, Aoki, Takumi
• Format: Journal Article
• Language: English
• Published: OXFORD Elsevier Ltd 01.11.2013; Elsevier
• Subjects: Alkanes - chemistry; Alkanes - pharmacology; Alkanes - therapeutic use; Animals; Antihypertensive Agents - chemistry; Antihypertensive Agents - pharmacology; Antihypertensive Agents - therapeutic use; Blood pressure; Blood Pressure - drug effects; Chemistry; Chemistry, Medicinal; Chemistry, Organic; Epoxide Hydrolases - antagonists & inhibitors; Epoxide Hydrolases - chemistry; Epoxide Hydrolases - metabolism; Humans; Hypertension; Hypertension - drug therapy; Hypertension - enzymology; Life Sciences & Biomedicine; Mean blood pressure; Molecular Docking Simulation; Pharmacology & Pharmacy; Physical Sciences; Rats; Rats, Inbred SHR; Science & Technology; sEH inhibitor; Spirocyclic diamine; Spontaneously hypertensive rat; Urea; Urea - analogs & derivatives; Urea - pharmacology; Urea - therapeutic use; Hypertension; Urea; Mean blood pressure; Spontaneously hypertensive rat; sEH inhibitor; Spirocyclic diamine; METABOLISM; EPOXYEICOSATRIENOIC ACIDS
• ISSN: 0960-894X; 1464-3405
• DOI: 10.1016/j.bmcl.2013.08.054

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.