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

Sampath Kumar Anandan, Heather Kay Webb, Dawn Chen, Yi Xin 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 MacIntyreJames Sabry, Richard Gless

Research output: Contribution to journalArticle

45 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)983-988
Number of pages6
JournalBioorganic and Medicinal Chemistry Letters
Volume21
Issue number3
DOIs
StatePublished - Feb 1 2011

Keywords

  • AngII hypertension model
  • AR9281
  • Diabetes
  • DIO model
  • Efficacy
  • sEH inhibitor

ASJC Scopus subject areas

  • Pharmaceutical Science
  • Drug Discovery
  • Organic Chemistry
  • Molecular Medicine
  • Molecular Biology
  • Clinical Biochemistry
  • Biochemistry

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  • Cite this

    Anandan, S. K., Webb, H. K., Chen, D., Wang, Y. X., Aavula, B. R., Cases, S., Cheng, Y., Do, Z. N., Mehra, U., Tran, V., Vincelette, J., Waszczuk, J., White, K., Wong, K. R., Zhang, L. N., Jones, P. D., Hammock, B. D., Patel, D. V., Whitcomb, R., ... Gless, R. (2011). 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. Bioorganic and Medicinal Chemistry Letters, 21(3), 983-988. https://doi.org/10.1016/j.bmcl.2010.12.042