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

  • Bioorg Med Chem Lett. 2011 Feb 1;21(3):983-8. doi: 10.1016/j.bmcl.2010.12.042.
Sampath-Kumar Anandan  1 ,  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
Affiliations
  • 1. Arête Therapeutics, Inc., 7000 Shoreline Court, South San Francisco, CA 94080, United States. [email protected]
PMID: 21211973 DOI: 10.1016/j.bmcl.2010.12.042
Abstract

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.