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

被引：69

作者：

Anandan, Sampath-Kumar ^{[1
]}

Webb, Heather Kay ^{[1
]}

Chen, Dawn ^{[1
]}

Wang, Yi-Xin ^{[1
]}

Aavula, Basker R. ^{[1
]}

Cases, Sylvaine ^{[1
]}

Cheng, Ying ^{[1
]}

Do, Zung N. ^{[1
]}

Mehra, Upasana ^{[1
]}

Vinh Tran ^{[1
]}

Vincelette, Jon ^{[1
]}

Waszczuk, Joanna ^{[1
]}

White, Kathy ^{[1
]}

Wong, Kenneth R. ^{[1
]}

Zhang, Le-Ning ^{[1
]}

Jones, Paul D. ^{[2
,3
]}

Hammock, Bruce D. ^{[2
,3
]}

Patel, Dinesh V. ^{[1
]}

Whitcomb, Randall ^{[1
]}

MacIntyre, D. Euan ^{[1
]}

Sabry, James ^{[1
]}

Gless, Richard ^{[1
]}

机构：

[1] Arete Therapeut Inc, San Francisco, CA 94080 USA

[2] Univ Calif Davis, Dept Entomol, Davis, CA 95616 USA

[3] Univ Calif Davis, UCD Canc Ctr, Davis, CA 95616 USA

来源：

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS | 2011年 / 21卷 / 03期

关键词：

sEH inhibitor; AR9281; Efficacy; DIO model; AngII hypertension model; Diabetes; EPOXYEICOSATRIENOIC ACIDS; INSULIN-RESISTANCE; 12-(3-ADAMANTAN-1-YL-UREIDO)DODECANOIC ACID; VASCULAR INFLAMMATION; BLOOD-PRESSURE; HIGHLY POTENT; PHARMACOKINETICS; METABOLISM; DISCOVERY; ATHEROSCLEROSIS;

D O I：

10.1016/j.bmcl.2010.12.042

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

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. (C) 2010 Elsevier Ltd. All rights reserved.

引用

页码：983 / 988

页数：6

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