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

https://doi.org/10.1016/j.bmcl.2010.12.042Get rights and content

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.

Graphical abstract

1-(1-Acetyl-piperidin-4-yl)-3-adamantan-1-yl-urea (AR9281) attenuated the enhanced glucose excursion following an intraperitoneal glucose tolerance test and the increase in blood pressure in angiotensin-II-induced hypertension in rats. These effects were dose-dependent and well correlated with inhibition of the soluble epoxide hydrolase (sEH) activity in whole blood.

  1. Download : Download full-size image

Section snippets

Acknowledgments

Partial support for P.D.J. and B.D.H. came from NIEHS R01 ES002710. B.D.H. is a George and Judy Marcus Senior Fellow of the American Asthma Foundation. P.D.J. was supported in part by an NIH/NHLBI Ruth L. Kirchstein NRSA Grant (F32 HL078096).

References and notes (36)

  • A randomized, double-blind, placebo-controlled, dose-ranging, exploratory, 28-day study to examine the effects of...
  • Z. Yu et al.

    Circ. Res.

    (2000)
  • K.R. Schmelzer et al.

    Proc. Natl. Acad. Sci.

    (2005)
  • B. Inceoglu et al.

    Life Sci.

    (2006)
    B. Inceoglu et al.

    Prostaglandins Other Lipid Mediat.

    (2007)
    B. Inceoglu et al.

    Proc. Natl. Acad. Sci. U.S.A.

    (2008)
  • D.C. Zeldin et al.

    J. Biol. Chem.

    (1993)
  • J. Wray et al.

    Exp. Physiol.

    (2008)
  • N.O. Rizzo et al.

    Arterioscler. Thromb. Vasc. Biol.

    (2010)
  • Chen, D.; Whitcomb, R.; MacIntyre, E.; Tran, V.; Do, Z. N.; Sabry, J.; Patel, D. V.; Anadan, S. K.; Gless, R.; Webb, H....
  • J.P. Marino

    Curr. Top. Med. Chem.

    (2009)
    H.C. Shen

    Expert Opin. Ther. Patents

    (2010)
  • P.D. Jones et al.

    Bioorg. Med. Chem. Lett.

    (2006)
    T.E. Rose et al.

    J. Med. Chem.

    (2010)
  • A.A. Spector et al.

    Am. J. Physiol. Cell Physiol.

    (2007)
    B.T. Lason et al.

    Eur. J. Clin. Invest.

    (2006)
    A.A. Spector et al.

    Prog. Lipid Res.

    (2004)
  • B.M. De Taeye et al.

    Obesity

    (2010)
    K. Sodhi et al.

    J. Pharmacol. Exp. Ther.

    (2009)
    K.P. Burdon et al.

    Diab. Vasc. Dis. Res.

    (2008)
    P. Luo et al.

    J. Pharmacol. Exp. Ther.

    (2010)
    S. Mustafa et al.

    Exp. Clin. Cardiol.

    (2009)
    A. Lyer et al.

    Nat. Rev. Endocrinol.

    (2010)
    K. Ohtoshi et al.

    Biochem. Biophys. Res. Commun.

    (2005)
    (h) Webb, H. WO 08058033 A2,...B.T. Larsen et al.

    Trends Pharmacol. Sci.

    (2007)
  • O. Jung et al.

    Hypertension

    (2005)
  • J.D. Imig et al.

    Hypertension

    (2005)
  • X. Zhao et al.

    J. Am. Soc. Nephrol.

    (2004)
    J.D. Imig

    Am. J. Physiol. Renal Physiol.

    (2005)
  • A.M. Dorrance et al.

    J. Cardiovasc. Pharmacol.

    (2005)
  • D. Xu et al.

    Proc. Natl. Acad. Sci.

    (2006)
  • (a)Liu, Y.; Webb, H.; Kroetz, D. L. FASEB J. 2008, 22,...A.R. Parrish et al.

    Cell Biol. Toxicol.

    (2009)
  • Cited by (0)

    View full text