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 MacIntyre; James Sabry; Richard Gless

doi:10.1016/j.bmcl.2010.12.042

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

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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 language	English (US)
Pages (from-to)	983-988
Number of pages	6
Journal	Bioorganic and Medicinal Chemistry Letters
Volume	21
Issue number	3
DOIs	https://doi.org/10.1016/j.bmcl.2010.12.042
State	Published - 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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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

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

In: Bioorganic and Medicinal Chemistry Letters, Vol. 21, No. 3, 01.02.2011, p. 983-988.

Research output: Contribution to journal › Article › peer-review

Anandan, SK, Webb, HK, Chen, D, Wang, YX, Aavula, BR, Cases, S, Cheng, Y, Do, ZN, Mehra, U, Tran, V, Vincelette, J, Waszczuk, J, White, K, Wong, KR, Zhang, LN, Jones, PD, Hammock, BD, Patel, DV, Whitcomb, R, MacIntyre, DE, Sabry, J & 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, vol. 21, no. 3, pp. 983-988. https://doi.org/10.1016/j.bmcl.2010.12.042

Anandan SK, Webb HK, Chen D, Wang YX, Aavula BR, Cases S et al. 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. 2011 Feb 1;21(3):983-988. https://doi.org/10.1016/j.bmcl.2010.12.042

Anandan, Sampath Kumar ; Webb, Heather Kay ; Chen, Dawn ; Wang, Yi Xin ; Aavula, Basker R. ; Cases, Sylvaine ; Cheng, Ying ; Do, Zung N. ; Mehra, Upasana ; Tran, Vinh ; Vincelette, Jon ; Waszczuk, Joanna ; White, Kathy ; Wong, Kenneth R. ; Zhang, Le Ning ; Jones, Paul D. ; Hammock, Bruce D. ; Patel, Dinesh V. ; Whitcomb, Randall ; MacIntyre, D. Euan ; Sabry, James ; Gless, Richard. / 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. In: Bioorganic and Medicinal Chemistry Letters. 2011 ; Vol. 21, No. 3. pp. 983-988.

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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.",

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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

Abstract

Keywords

ASJC Scopus subject areas

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