1-(1-Acetyl-piperidin-4-yl)-3-adamantan-1-yl-urea (AR9281) as a potent, selective, and orally available soluble epoxide hydrolase inhibitor with efficacy in rodent models of hypertension and dysglycemia

✍ Scribed by Sampath-Kumar Anandan; Heather Kay Webb; Dawn Chen; Yi-Xin (Jim) Wang; Basker R. Aavula; Sylvaine Cases; Ying Cheng; Zung N. Do; Upasana Mehra; Vinh Tran; Jon Vincelette; Joanna Waszczuk; Kathy White; Kenneth R. Wong; Le-Ning Zhang; Paul D. Jones; Bruce D. Hammock; Dinesh V. Patel; Randall Whitcomb; D. Euan MacIntyre; James Sabry; Richard Gless

• Book ID: 104005223
• Publisher: Elsevier Science
• Year: 2011
• Tongue: English
• Weight: 339 KB
• Volume: 21
• Category: Article
• ISSN: 0960-894X
• DOI: 10.1016/j.bmcl.2010.12.042

✦ Synopsis

1-(1-Acetyl-piperidin-4-yl)-3-adamantan-1-yl-urea 14a (AR9281), a potent and selective soluble epoxide hydrolase inhibitor, was recently tested in a phase 2a clinical setting for its effectiveness in reducing blood pressure and improving insulin resistance in pre-diabetic patients. In a mouse model of diet induced obesity, AR9281 attenuated the enhanced glucose excursion following an intraperitoneal glucose tolerance test. AR9281 also attenuated the increase in blood pressure in angiotensin-II-induced hypertension in rats. These effects were dose-dependent and well correlated with inhibition of the sEH activity in whole blood, consistent with a role of sEH in the observed pharmacology in rodents.