Tezosentan (RO 610612)
(Synonyms: RO 610612) 目录号 : GC30942
Tezosentan (RO 610612) (RO 610612) 是一种内皮素 (ET) 受体拮抗剂，ETA 和 ETB 受体的 pA2 分别为 9.5、7.7。
Cas No.:180384-57-0
Sample solution is provided at 25 µL, 10mM.
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- Purity: >98.00%
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Animal experiment: | Rats[1]A pseudocrush syndrome is simulated by injection of i.m. glycerol. A control group does not receive glycerol and is used as a reference. Tezosentan or bosentan for comparison or saline as control is injected as two bolus i.v. doses of 10 mg/kg 1 h and 20 min before glycerol. Rats are allowed to recover for 2 h and then are placed in individual metabolic cages for 48 h. Blood samples withdraw from a catheter placed in the abdominal aorta and urine free of food and feces are collected at 24 and 48 h. Plasma and urinary creatinine levels are measured with a centrifugal analyzer. Renal function is assessed by calculating creatinine clearance at 24 and 48 h after glycerol administration[1]. |
References: [1]. Clozel M, et al. Pharmacology of tezosentan, new endothelin receptor antagonist designed for parenteral use. J Pharmacol Exp Ther. 1999 Aug;290(2):840-6. | |
Tezosentan (RO 610612) is an endothelin (ET) receptor antagonist, with pA2s of 9.5, 7.7 for ETA and ETB receptors, respectively.
Affinity of Tezosentan for the ET receptors is assessed in different cells and tissues. Tezosentan inhibits the specific 125I-labeled ET-1 binding to ETA receptors with an inhibitory potency (Ki) of 0.3 nM on CHO cells and of 18 nM on membranes of baculovirus-infected insect cells. Similarly, Tezosentan inhibits the specific binding of 125I-labeled ET-1, ET-3, or sarafotoxin S6c to ETB receptors with an inhibitory affinity of 10 to 21 nM. Tezosentan up to a concentration of 1 μM did not exhibit any binding inhibitory activity in 27 radioligand binding assays different from ET binding. On H1 central, 5-hydroxytryptamine2A, and vasopressin V1 receptors, Tezosentan (1 μM) induces a weak inhibition of less than 20%[1].
In pithed Wistar rats, Tezosentan dose-dependently inhibits the pressor effect of big ET-1 (P<0.001 at all doses). At the lowest dose tested of 1 mg/kg, Tezosentan inhibits the pressor effect of the various doses of big ET-1 by 50 to 80%. Tezosentan has no effect by itself on blood pressure in these pithed rats. Tezosentan is very effective in a rat model of acute renal failure. ET antagonists have been shown to prevent the vasoconstriction and the renal failure that follow acute renal ischemia in rats[1].
[1]. Clozel M, et al. Pharmacology of tezosentan, new endothelin receptor antagonist designed for parenteral use. J Pharmacol Exp Ther. 1999 Aug;290(2):840-6.
| Cas No. | 180384-57-0 | SDF | |
| 别名 | RO 610612 | ||
| Canonical SMILES | O=S(C1=NC=C(C(C)C)C=C1)(NC2=NC(C3=CC(C4=NNN=N4)=NC=C3)=NC(OCCO)=C2OC5=CC=CC=C5OC)=O | ||
| 分子式 | C27H27N9O6S | 分子量 | 605.63 |
| 溶解度 | Soluble in DMSO | 储存条件 | Store at -20°C |
| General tips | 请根据产品在不同溶剂中的溶解度选择合适的溶剂配制储备液；一旦配成溶液，请分装保存，避免反复冻融造成的产品失效。 储备液的保存方式和期限：-80°C 储存时，请在 6 个月内使用，-20°C 储存时，请在 1 个月内使用。 为了提高溶解度，请将管子加热至37℃，然后在超声波浴中震荡一段时间。 |
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1 mg | 5 mg | 10 mg |
| 1 mM | 1.6512 mL | 8.2559 mL | 16.5117 mL |
| 5 mM | 0.3302 mL | 1.6512 mL | 3.3023 mL |
| 10 mM | 0.1651 mL | 0.8256 mL | 1.6512 mL |
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动物平均体重 | g | |
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动物数量 | 只 |
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RO 610612
Endothelin receptor antagonism by tezosentan attenuates lung injury induced by aortic ischemia-reperfusion
Tezosentan is a novel dual endothelin receptor antagonist. The purpose of this study was to examine the effect of tezosentan on lung injury induced by abdominal aortic ischemia-reperfusion (IR) in rats. Thirty-two Wistar-albino rats were randomized into four groups (eight per group) as follows: control group (sham laparotomy), aortic IR group (120 min ischemia and 120 min reperfusion), aortic IR + tezosentan group (a bolus intravenous injection of 10 mg/kg tezosentan before ischemia plus continuous intravenous infusion of 1 mg/kg/hr tezosentan during 120 min ischemia and 120 min reperfusion), and control + tezosentan. Blood and lung tissue samples were obtained for biochemical analysis. Protein concentrations in bronchoalveolar lavage fluid and lung wet/dry weight ratios were measured. A histological evaluation was also done. Aortic IR significantly increased (p < 0.05 vs. control group) and tezosentan significantly decreased (p < 0.05 vs. aortic IR group) the plasma level of tumor necrosis factor-alpha; lung tissue levels of malondialdehyde, catalase, and myleperoxidase; and protein concentration in bronchoalveolar lavage fluid and lung wet/dry weight ratio. Histological evaluation showed that tezosentan attenuated the morphological changes associated with lung injury. The results of this study indicate that tezosentan attenuates lung injury induced by aortic IR in rats. We propose that this protective effect of tezosentan is due to (1) reduced systemic inflammatory response, (2) reduced oxidative stress and lipid peroxidation in lung tissue, (3) reduced pulmonary microvascular leakage, and (4) inhibition of leukocyte infiltration into lung tissue.
Tezosentan in the treatment of acute heart failure
Objective: To evaluate the pharmacology, pharmacokinetics, clinical efficacy, and tolerability of tezosentan, a new intravenous endothelin (ET)-1 receptor antagonist.
Data sources: Literature was identified through a MEDLINE search (1990-June 2003) using the search terms endothelin-1, heart failure, RITZ, and tezosentan. References listed in articles and abstracts from scientific meetings were also used.
Study selection and data extraction: English-language literature reporting controlled animal and human clinical studies was reviewed to evaluate the pharmacology, pharmacokinetics, therapeutic use, and adverse effects of tezosentan. Clinical trials selected for inclusion were limited to those with human subjects and included data from animal studies if human data were not available.
Data synthesis: Tezosentan is a dual ET-1 receptor antagonist that has demonstrated efficacy in improving cardiac index and reducing pulmonary capillary wedge pressure in patients with acute, decompensated heart failure. Following infusion, tezosentan's plasma concentration approaches steady-state within the first 6 hours, with a relatively small volume of distribution (17 L) and clearance (39 L/h) that are dose independent. Tezosentan is excreted almost entirely unchanged via the bile (>95%), with the rest (<5%) excreted in the urine. Elimination can be explained by a biphasic profile that has a rapid elimination phase (half-life 6 min) followed by a slow phase (half-life 3 h) that accounts for distribution from tissues. The adverse event profile is significant for a higher incidence of headaches, nausea, and hypotension compared with placebo.
Conclusions: Phase II and III clinical trials have rendered mixed results for the efficacy and tolerability of tezosentan. A dose optimization trial yet to be published and an ongoing Phase III registration study will provide valuable data regarding the efficacy and tolerability benefits, as well as the morbidity and mortality, of tezosentan. Until then, tezosentan's role in the treatment of patients with acute heart failure will remain unclear.
Tezosentan in the management of decompensated heart failure
Decompensated heart failure continues to significantly impact the economics of our healthcare system. In recent years, the focus on management of decompensated heart failure has changed from solely improving hemodynamics to modifying neurohormones. Endothelin (ET) is one of the important mediators in heart failure. This article reviews the clinical pharmacology, clinical efficacy, and tolerability of tezosentan, a dual-action ET-1 receptor antagonist. Using the search term tezosentan, a literature review was conducted to identify peer-reviewed articles and abstracts in MEDLINE (1966 to April 2004) and Current Content (1966 to April 2004) databases. Citations from available articles were also reviewed for additional references. When given as an intravenous infusion, tezosentan achieves steady-state concentration within the first 6 hours. Tezosentan is excreted almost entirely through the bile (>95%) and has a terminal elimination half-life of 3 hours. The side effects of tezosentan include headache, nausea, and hypotension. Clinical studies demonstrated mixed results for tezosentan regarding its efficacy and tolerability in the management of decompensated heart failure. The role or tezosentan in treating heart failure is yet to be defined.
Tezosentan attenuates organ injury and mesenteric blood flow decrease in endotoxemia and cecal ligation and puncture
Background: Decreased mesenteric blood flow and multiple organ injury due to free radicals are the consequences of septic shock. Since the blockade of endothelin receptors was reported to exert beneficial effects, we investigated the effects of tezosentan, a novel dual endothelin receptor antagonist, in two different experimental models of septic shock induced either by the injection of Escherichia coli endotoxin (ETX, 20 mg/kg, i.p.) or by cecal ligation and puncture (CLP).
Study design: Swiss albino mice received tezosentan (10 mg/kg, i.p.) or its solvent saline (0.9% NaCl, w/v) twice at 2 and 22 h after ETX or CLP. At 24 h, the animals were anesthetized and the mesenteric blood flow was monitored for 15 min by using perivascular ultrasonic Doppler flowmeter. Then the animals were exsanguinated, and spleen, liver, and kidneys were isolated accordingly for histopathological examination. Thiobarbituric acid reacting substances and glutathione and myeloperoxides activities were also determined in the liver.
Results: In both ETX and CLP models, there was a decrease in mesenteric blood flow which was blocked by tezosentan. Similarly, tezosentan significantly attenuated the histopathological injury inflicted by both models. Although the glutathione levels were decreased and thiobarbituric acid reacting substances and myeloperoxidase activity were increased by ETX and CLP, tezosentan has failed to block these alterations in a consistent manner. However, a significant interaction between CLP and tezosentan with regard to myeloperoxidase activity and glutathione should be taken as partial evidence to explain the underlying mechanism of protection offered by tezosentan against liver injury.
Conclusions: Therefore, we concluded that tezosentan, by working via mechanisms mostly other than the blockade of free radical induced damage, is a useful treatment option for combating the deleterious effects of septic shock such as mesenteric ischemia as well as liver, spleen, and kidney injury.