HET0016, a potent and selective inhibitor of 20‐HETE synthesizing enzyme

Miyata, Noriyuki; Taniguchi, Kazuo; Seki, Takayuki; Ishimoto, Tsuyoshi; Sato-Watanabe, Mariko; Yasuda, Yoshiko; Doi, Mariko; Kametani, S.; Tomishima, Yasumitsu; Ueki, Tomokazu; Sato, Masakazu; Kameo, Kazuya

doi:10.1038/sj.bjp.0704101

Cited by 182 publications

(173 citation statements)

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“…2, a and b). This is an order of magnitude lower concentration than the reported IC 50 for HET0016 (Miyata et al, 2001). TS-011 is a 100 to 1000 times more potent inhibitor of the formation of 20-HETE than DDMS, ABT, 17-ODYA, or 10-SUYS (Wang et al, 1998;Su et al, 1998;Miyata et al, 2001;Xu et al, 2002).…”

Section: Discussionmentioning

confidence: 81%

“…Nevertheless, the currently available 20-HETE inhibitors have limited potential as therapeutics agents for the treatment of stroke and vasospasm. For example, DDMS, 17-ODYA, ABT, and 10-SUYS are not very potent or selective inhibitors of the synthesis of 20-HETE (Wang et al, 1998;Su et al, 1998;Miyata et al, 2001;Xu et al, 2002). They inhibit both the synthesis of 20-HETE and EETs.…”

Section: Discussionmentioning

confidence: 99%

“…The current available compounds, dibromododecinoic acid (DDMS), 17-ODYA, 1-aminobenzotriazol (ABT), or sodium 10-undecynyl sulfate (10-SUYS), are not very potent, and/or selective inhibitors for synthesis of 20-HETE (Su et al, 1998;Wang et al, 1998;Miyata et al, 2001;Xu et al, 2002) and 20-HETE antagonists are ineffective because they do not cross the blood brain barrier. HET0016 is the most selective inhibitor of the synthesis of 20-HETE (Miyata et al, 2001). However, this compound is not very soluble and has a limited half-life (Nakamura et al, 2003).…”

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confidence: 99%

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Beneficial Effects of a New 20-Hydroxyeicosatetraenoic Acid Synthesis Inhibitor, TS-011 [N-(3-Chloro-4-morpholin-4-yl) Phenyl-N′-hydroxyimido Formamide], on Hemorrhagic and Ischemic Stroke

Miyata

Seki²,

Tanaka³

et al. 2005

J Pharmacol Exp Ther

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The present study characterized the effects of TS-011 [N-(3-chloro-4-morpholin-4-yl) phenyl-NЈ-hydroxyimido formamide], a new selective inhibitor of the synthesis of 20-hydroxyeicosatetraenoic acid (20-HETE), on the metabolism of arachidonic acid by human and rat renal microsomes and the inhibitory effects of this compound on hepatic cytochrome P450 enzymes involved in drug metabolism. The effects of TS-011 on the fall in cerebral blood flow following subarachnoid hemorrhage (SAH) and in reducing infarct size in ischemic stroke models were also examined since 20-HETE may contribute to the development of cerebral vasospasm. TS-011 inhibited the synthesis of 20-HETE by human renal microsomes and recombinant CYP4A11 and 4F2, 4F3A, and 4F3B enzymes with IC 50 values around 10 to 50 nM. It had no effect on the activities of CYP1A, 2C9, 2C19, 2D6, or 3A4 enzymes. TS-011 inhibited the synthesis of 20-HETE by rat renal microsomes with an IC 50 of 9.19 nM, and it had no effect on epoxygenase activity at a concentration of 100 M. TS-011 (0.01-1 mg/kg i.v.) reversed the fall in cerebral blood flow and the increase in 20-HETE levels in the cerebrospinal fluid of rats after SAH. TS-011 also reduced the infarct volume by 35% following transient ischemic stroke and in intracerebral hemorrhage in rats. Injection of 20-HETE (8 or 12 mg/kg) into the carotid artery produced an infarct similar to that seen in the ischemic stroke model. These studies indicate that blockade of the synthesis of 20-HETE with TS-011 opposes cerebral vasospasm following SAH and reduces infarct size in ischemic models of stroke.Each year, 750,000 strokes occur in the United States. Approximately 80% of the strokes are ischemic, and 20% are hemorrhagic. Hemorrhagic stroke commonly occurs after rupture of aneurysms or head trauma. There is an initial period of cerebral ischemia lasting several hours due to a rise in cerebral spinal fluid (CSF) pressure and acute cerebral vasospasm. One-half of the patients that survive later develop delayed vasospasm. The mortality in the 1st month hovers around 50%. The majority of deaths (Ͼ60%) occur during the first 2 days and is associated with ischemic brain injury (Broderick et al., 1994). The factors that contribute to the acute fall in cerebral blood flow following subarachnoid hemorrhage (SAH) remain uncertain.Ischemic strokes are caused by blockage of cerebral arteries. In the ischemic neuronal tissue, there is depletion of

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Section: Discussionmentioning

confidence: 81%

Section: Discussionmentioning

confidence: 99%

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confidence: 99%

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Beneficial Effects of a New 20-Hydroxyeicosatetraenoic Acid Synthesis Inhibitor, TS-011 [N-(3-Chloro-4-morpholin-4-yl) Phenyl-N′-hydroxyimido Formamide], on Hemorrhagic and Ischemic Stroke

Miyata

Seki²,

Tanaka³

et al. 2005

J Pharmacol Exp Ther

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“…Dibromo-olefinic fatty acids are relatively specific inhibitors of arachidonic acid -/( -1)-hydroxylation and have been extensively used to characterize 20-HETE biological effects in vitro and in situ (17,21,46,54). The most potent inhibitor of arachidonic acid -hydroxylation to date is N-hydroxy-NЈ-(4-butyl-2-methylphenyl)-formamidine (HET-0016) (33). HET-0016 inhibits 20-HETE formation in rat renal microsomes with an IC 50 of 35 nM, while epoxygenation is relatively resistant to inhibition.…”

Section: Discussionmentioning

confidence: 99%

Antihypertensive effect of mechanism-based inhibition of renal arachidonic acid ω-hydroxylase activity

Xu¹,

Straub

Pak³

et al. 2002

American Journal of Physiology-Regulatory, Integrative and Comp

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is a potent vasoconstrictor that is implicated in the regulation of blood pressure. The identification of selective inhibitors of renal 20-HETE formation for use in vivo would facilitate studies to determine the systemic effects of this eicosanoid. We characterized the acetylenic fatty acid sodium 10-undecynyl sulfate (10-SUYS) as a potent and selective mechanism-based inhibitor of renal 20-HETE formation. A single dose of 10-SUYS caused an acute reduction in mean arterial blood pressure in 8-wk-old spontaneously hypertensive rats. The decrease in mean arterial pressure was maximal 6 h after 10-SUYS treatment (17.9 Ϯ 3.2 mmHg; P Ͻ 0.05), and blood pressure returned to baseline levels within 24 h after treatment. Treatment with 10-SUYS was associated with a decrease in urinary 20-HETE formation in vivo and attenuation of the vasoconstrictor response of renal interlobar arteries to ANG II in vitro. These results provide further evidence that 20-HETE plays an important role in the regulation of blood pressure in the spontaneously hypertensive rat.spontaneously hypertensive rat; cytochrome P-450; sodium 10-undecynyl sulfate; 20-hydroxyeicosatetraenoic acid CYTOCHROMES P-450 (CYPs) are major catalysts of renal arachidonic acid metabolism, and CYP-derived eicosanoids have been implicated in the regulation of vascular tone and renal function (9, 41). The major products of CYP-catalyzed arachidonic acid metabolism are the -hydroxylated metabolite 20-hydroxyeicosatetraenoic acid (20-HETE) and four regio-and stereoisomeric epoxyeicosatrienoic acids (EETs). EETs are further hydrated to the corresponding dihydroxyeicosatrienoic acids (DHETs) by soluble epoxide hydrolase (sEH) (53). The major CYP eicosanoid formed in rat and human renal microsomes is 20-HETE (8, 28). 20-HETE depolarizes vascular smooth muscle cells by inhibiting Ca 2ϩ -activated K ϩ channels and increases the conductance of L-type Ca 2ϩ channels, both effects leading to Ca 2ϩ entry and potent vasoconstriction (14,56). Additional roles for 20-HETE include mediation of the myogenic response of small cerebral and renal arteries to elevations in transmural pressure, and the autoregulation of cerebral and renal blood flow, glomerular filtration rate, and tubular glomerular feedback (13,22,58). In renal tubules 20-HETE inhibits Na ϩ -K ϩ -ATPase, a Na ϩ -K ϩ -2Cl Ϫ cotransporter, and 70-pS K ϩ channels, leading to natriuresis and diuresis (3,30,38). EETs and DHETs are generally considered vasodilatory, although they exhibit both vasodilatory and vasoconstrictive properties in vitro, depending on the vascular bed and species that are studied (20,55,57). A number of studies suggest that EETs are endothelium-derived hyperpolarizing factors that mediate vasodilation by activation of Ca 2ϩ -dependent K ϩ channels in vascular smooth muscle cells (6,7,10). Both EETs and DHETs can also mediate natriuresis and diuresis by inhibition of Na ϩ -K ϩ -ATPase in rat proximal tubules (38).The effects of CYP eicosanoids in the regulation of vascular tone and renal function have pr...

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“…More recently, 1-aminobenzotriazole (ABT) has been reported to reduce the renal formation of 20-HETE and/or EETs when given acutely to rats, 10,12,13 and N-hydroxy-NЈ-(4-butyl-2 methylphenyl) formamidine (HET0016) has been shown to be the most selective inhibitor of the renal formation of 20-HETE. 14 Therefore, in the current study, we examined the effects of chronic administration of ABT and HET0016 on the renal metabolism of AA, the urinary excretion of 20-HETE, and blood pressure in Sprague-Dawley (SD) rats fed a low or a high salt diet.…”

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Inhibitors of 20-HETE Formation Promote Salt-Sensitive Hypertension in Rats

2003

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Abstract-This study examined whether chronic blockade of epoxyeicosatrienoic acids (EETs) and/or 20-hydroxyeicosatetraenoic acid (20-HETE) formation promotes development of salt-sensitive hypertension. Changes in blood pressure, renal cytochrome P450 metabolism of arachidonic acid, and 20-HETE excretion in response to a high salt diet were measured in rats chronically treated with 1-aminobenzotriazole (ABT, 50 mg/kg per day) to block EETs and 20-HETE formation or N-hydroxy-NЈ-(4-butyl-2 methylphenyl) formamidine (HET0016, 10 mg/kg per day) that selectively reduces 20-HETE formation. ABT reduced blood pressure in rats fed a low salt (0.4% NaCl) diet, but blood pressure rose by 20 mm Hg after these rats were switched to a high salt (8% NaCl) diet for 10 days. HET0016 had no effect on blood pressure in rats fed a low salt diet; however, blood pressure rose by 18 mm Hg after the rats were fed a high salt diet. 20-HETE formation in kidney homogenates rose by 30% and epoxygenase activity doubled when rats were fed a high salt diet. Chronic treatment with ABT and HET0016 inhibited the renal formation of 20-HETE by Ϸ90%. Renal epoxygenase activity decreased by 76% in ABT-treated rats and was not significantly altered in rats treated with HET0016. 20-HETE excretion rose from 470Ϯ21 to 570Ϯ41 ng/d when the rats were switched from the low to the high salt diet. 20-HETE excretion fell by 68% and 85% in rats that were chronically treated with ABT and HET0016. These results suggest that chronic blockade of the formation of 20-HETE promotes the development of salt-sensitive hypertension in rats. Key Words: rats, Dahl Ⅲ metabolism Ⅲ arachidonic acids Ⅲ blood pressure Ⅲ hypertension, sodium-dependent T he role of the cytochrome P450 (P450) metabolites of arachidonic acid (AA) in the development and maintenance of hypertension remains uncertain in part because this pathway has both prohypertensive and antihypertensive actions. 1 20-Hydroxyeicosatetraenoic acid (20-HETE) inhibits Na ϩ transport in the proximal tubule and thick ascending limb of the loop of Henle (TALH), 2-5 and compounds that induce the renal formation of 20-HETE lower blood pressure in Dahl salt-sensitive (DS) rats. 1 Similarly, epoxyeicosatrienoic acids (EETs) inhibit Na ϩ transport in the proximal tubule and collecting duct, 6,7 and increasing the renal levels of EETs with inhibitors of soluble epoxide hydrolase (sEH) reduces blood pressure in spontaneously hypertensive rats (SHRs) 8 and angiotensin II-induced hypertensive rats. 9 However, 20-HETE is also a potent vasoconstrictor, 1 and many investigators have reported that blocking the vascular effects of 20-HETE may contribute to its antihypertensive effect in SHR and other experimental models of hypertension. 10,11 Part of the problem in defining the role of the P450 metabolites of AA in the control of blood pressure has been the lack of selective inhibitors of the pathway that chronically block the formation of 20-HETE and EETs in vivo. Inhibitors that are commonly used to inhibit the formation of EETs and ...

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HET0016, a potent and selective inhibitor of 20‐HETE synthesizing enzyme

Cited by 182 publications

References 18 publications

Beneficial Effects of a New 20-Hydroxyeicosatetraenoic Acid Synthesis Inhibitor, TS-011 [N-(3-Chloro-4-morpholin-4-yl) Phenyl-N′-hydroxyimido Formamide], on Hemorrhagic and Ischemic Stroke

Beneficial Effects of a New 20-Hydroxyeicosatetraenoic Acid Synthesis Inhibitor, TS-011 [N-(3-Chloro-4-morpholin-4-yl) Phenyl-N′-hydroxyimido Formamide], on Hemorrhagic and Ischemic Stroke

Antihypertensive effect of mechanism-based inhibition of renal arachidonic acid ω-hydroxylase activity

Inhibitors of 20-HETE Formation Promote Salt-Sensitive Hypertension in Rats

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