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 K.; Chen, Dawn; Wang, Yi-Xin Jim; Aavula, Basker R; Cases, Sylvaine; Cheng, Ying; 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 W.; MacIntyre, D. Euan; Sabry, James; Gless, Richard D.

doi:10.1016/j.bmcl.2010.12.042

Cited by 67 publications

(53 citation statements)

References 53 publications

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“…Whereas AUDA and structurally related sEH inhibitors reduce blood pressure in hypertensive rats (spontaneously hypertensive rats [SHR] and angiotensin II infusion models), GSK2188931 and GSK2256294 did not reduce right carotid artery pressure in this study or systemic blood pressure in previous rodent studies. [17][18][19][20][21] Consistent with GSK2188931 and GSK2256294, sEH inhibitors with similar structure and inhibitory activity to these compounds also failed to reduce blood pressure in hypertensive rats (angiotensin-II infusion and SHR, unpublished results). Similar results were independently reported by others, where potent and selective sEH inhibitors did not lower blood pressure in SHR.…”

Section: Discussionmentioning

confidence: 64%

“…6,16 However, sEH inhibitors tested in chronic pressure overload models of HF reduce blood pressure in hypertensive rats. 5,[17][18][19][20][21] Curiously, several recently described potent and selective sEH inhibitors failed to lower blood pressure in hypertensive rats, raising the possibility that sEH inhibition does not play a role in blood pressure regulation. 22,23 Considering that 63% of HFpEF patients exhibit hypertension, discerning the role of sEH on blood pressure regulation might be pivotal for determining whether sEH inhibition will be of utility for this patient population.…”

Section: Introductionmentioning

confidence: 99%

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Soluble Epoxide Hydrolase Inhibition Does Not Prevent Cardiac Remodeling and Dysfunction After Aortic Constriction in Rats and Mice

Morgan

Olzinski

Upson

et al. 2013

Journal of Cardiovascular Pharmacology

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Epoxyeicosatrienoic acids, substrates for soluble epoxide hydrolase (sEH), exhibit vasodilatory and antihypertrophic activities. Inhibitors of sEH might therefore hold promise as heart failure therapeutics. We examined the ability of sEH inhibitors GSK2188931 and GSK2256294 to modulate cardiac hypertrophy, fibrosis, and function after transverse aortic constriction (TAC) in rats and mice. GSK2188931 administration was initiated in rats 1 day before TAC, whereas GSK2256294 treatment was initiated in mice 2 weeks after TAC. Four weeks later, cardiovascular function was assessed, plasma was collected for drug and sEH biomarker concentrations, and left ventricle was isolated for messenger RNA and histological analyses. In rats, although GSK2188931 prevented TAC-mediated increases in certain genes associated with hypertrophy and fibrosis (α-skeletal actin and connective tissue growth factor), the compound failed to attenuate TAC-induced increases in left ventricle mass, posterior wall thickness, end-diastolic volume and pressure, and perivascular fibrosis. Similarly, in mice, GSK2256294 did not reverse cardiac remodeling or systolic dysfunction induced by TAC. Both compounds increased the sEH substrate/product (leukotoxin/leukotoxin diol) ratio, indicating sEH inhibition. In summary, sEH inhibition does not prevent cardiac remodeling or dysfunction after TAC. Thus, targeting sEH seems to be insufficient for reducing pressure overload hypertrophy.

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Section: Discussionmentioning

confidence: 64%

Section: Introductionmentioning

confidence: 99%

Soluble Epoxide Hydrolase Inhibition Does Not Prevent Cardiac Remodeling and Dysfunction After Aortic Constriction in Rats and Mice

Morgan

Olzinski

Upson

et al. 2013

Journal of Cardiovascular Pharmacology

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“…In obese and IR hemeoxygenase-deficient mice, all EET isomers were noted to be severely reduced, and inhibition of sEH improved both BP and glucose disposal during insulin challenge (38). In rat and murine models of diet-induced IR, treatment with an sEH inhibitor improved glucose storage after insulin administration or after glucose challenge (1,22). There have been several other studies confirming that either sEH inhibition or gene-targeted therapies that increase EETs (either CYP-2J3 gene therapy or sEH deletion) Values are means Ϯ SE.…”

Section: Discussionmentioning

confidence: 99%

Epoxyeicosatrienoic acids mediate insulin-mediated augmentation in skeletal muscle perfusion and blood volume

Shim¹,

Kim²,

Chadderdon³

et al. 2014

American Journal of Physiology-Endocrinology and Metabolism

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Skeletal muscle microvascular blood flow (MBF) increases in response to physiological hyperinsulinemia. This vascular action of insulin may facilitate glucose uptake. We hypothesized that epoxyeicosatrienoic acids (EETs), a family of arachadonic, acid-derived, endothelium-derived hyperpolarizing factors, are mediators of insulin's microvascular effects. Contrast-enhanced ultrasound (CEU) was performed to quantify skeletal muscle capillary blood volume (CBV) and MBF in wild-type and obese insulin-resistant (db/db) mice after administration of vehicle or trans-4- [4-(3-adamantan-1-ylureido)cyclohexyloxy]benzoic acid (t-AUCB), an inhibitor of soluble epoxide hydrolase that converts EETs to less active dihydroxyeicosatrienoic acids. Similar studies were performed in rats pretreated with L-NAME. CEU was also performed in rats undergoing a euglycemic hyperinsulinemic clamp, half of which were pretreated with the epoxygenase inhibitor MS-PPOH to inhibit EET synthesis. In both wild-type and db/db mice, intravenous t-AUCB produced an increase in CBV (65-100% increase at 30 min, P Ͻ 0.05) and in MBF. In db/db mice, t-AUCB also reduced plasma glucose by ϳ15%. In rats pretreated with L-NAME, t-AUCB after produced a significant Ϸ20% increase in CBV, indicating a component of vascular response independent of nitric oxide (NO) production. Hyperinsulinemic clamp produced a time-dependent increase in MBF (19 Ϯ 36 and 76 Ϯ 49% at 90 min, P ϭ 0.026) that was mediated in part by an increase in CBV. Insulin-mediated changes in both CBV and MBF during the clamp were blocked entirely by MS-PPOH. We conclude that EETs are a mediator of insulinmediated augmentation in skeletal muscle perfusion and are involved in regulating changes in CBV during hyperinsulinemia.

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“…99 Preclinical studies have shown that inhibitors of s-EH lower BP, prevent and reverse pressure overload-induced cardiac hypertrophy, attenuate ischemic and ischemia-reperfusion injury of the brain and heart, prevent atherosclerosis and aneurysm formation, and attenuate insulin resistance in animal models. [98][99][100] AR9281 is a potent and selective inhibitor of human s-EH that has been shown to lower BP, improve vascular function, and reduce renal damage in a rat model of Ang II-induced hypertension 101 and to improve glycemic parameters in a mouse model of diet-induced obesity 102 (Table). The metabolic effects of AR9281 were absent in mice with diet-induced obesity due to deletion of the Ephx2 gene, which encodes s-EH, validating the mechanism of the AR9281 effect.…”

Section: Soluble Epoxide Hydrolase Inhibitorsmentioning

confidence: 99%

New Approaches in the Treatment of Hypertension

Oparil

Schmieder

2015

Circulation Research

242

137

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Hypertension is the most common modifiable risk factor for cardiovascular disease and death, and lowering blood pressure with antihypertensive drugs reduces target organ damage and prevents cardiovascular disease outcomes. Despite a plethora of available treatment options, a substantial portion of the hypertensive population has uncontrolled blood pressure. The unmet need of controlling blood pressure in this population may be addressed, in part, by developing new drugs and devices/procedures to treat hypertension and its comorbidities. In this Compendium Review, we discuss new drugs and interventional treatments that are undergoing preclinical or clinical testing for hypertension treatment. New drug classes, eg, inhibitors of vasopeptidases, aldosterone synthase and soluble epoxide hydrolase, agonists of natriuretic peptide A and vasoactive intestinal peptide receptor 2, and a novel mineralocorticoid receptor antagonist are in phase II/III of development, while inhibitors of aminopeptidase A, dopamine β-hydroxylase, and the intestinal Na + /H + exchanger 3, agonists of components of the angiotensin-converting enzyme 2/angiotensin(1–7)/Mas receptor axis and vaccines directed toward angiotensin II and its type 1 receptor are in phase I or preclinical development. The two main interventional approaches, transcatheter renal denervation and baroreflex activation therapy, are used in clinical practice for severe treatment resistant hypertension in some countries. Renal denervation is also being evaluated for treatment of various comorbidities, eg, chronic heart failure, cardiac arrhythmias and chronic renal failure. Novel interventional approaches in early development include carotid body ablation and arteriovenous fistula placement. Importantly, none of these novel drug or device treatments has been shown to prevent cardiovascular disease outcomes or death in hypertensive patients.

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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

Cited by 67 publications

References 53 publications

Soluble Epoxide Hydrolase Inhibition Does Not Prevent Cardiac Remodeling and Dysfunction After Aortic Constriction in Rats and Mice

Soluble Epoxide Hydrolase Inhibition Does Not Prevent Cardiac Remodeling and Dysfunction After Aortic Constriction in Rats and Mice

Epoxyeicosatrienoic acids mediate insulin-mediated augmentation in skeletal muscle perfusion and blood volume

New Approaches in the Treatment of Hypertension

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