Tasosartan (WAY-ANA 756)
(Synonyms: 他索沙坦,WAY-ANA 756) 目录号 : GC32507
An AT2 receptor antagonist
Cas No.:145733-36-4
Sample solution is provided at 25 µL, 10mM.
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Quality Control & SDS
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- Purity: >99.00%
- COA (Certificate Of Analysis)
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Animal experiment: | Rats[2]Pressor response to angiotensin-II administration in four groups of rats (n=3-5 each, weighing 343±8 g). Each rat is subjected to four separate bolus injections of angiotensin-II following the introduction of either the vehicle or graded doses of Tasosartan (0.3, 1.0, or 3.0 mg/kg, iv)[2]. |
References: [1]. Maillard MP, et al. Tasosartan, enoltasosartan, and angiotensin II receptor blockade: the confounding role of protein binding. J Pharmacol Exp Ther. 2000 Nov;295(2):649-54. | |
Tasosartan is an angiotensin II type 2 (AT2) receptor antagonist (IC50 = 1.2 nM in rat adrenal gland membranes).1 It also binds to the AT1 receptor (Ki = 46.6 nM in rat liver epithelial cells).2 Tasosartan (3 mg/kg, intraduodenally) reduces the AT2-induced pressor response in rats.3 It also decreases mean arterial pressure in a rat model of hypertension induced by renal artery constriction when administered intragastrically or intravenously at doses of 1 and 3 mg/kg.1
1.Ellingboe, J.W., Collini, M.D., Quagliato, D., et al.Metabolites of the angiotensin II antagonist tasosartan: The importance of a second acidic groupJ. Med. Chem.41(22)4251-4260(1998) 2.Hines, J., Fluharty, S.J., and Sakai, R.R.The angiotensin AT1 receptor antagonist irbesartan has near-peptide affinity and potently blocks receptor signalingEur. J. Pharmacol.384(1)81-89(1999) 3.Ellingboe, J.W., Antane, M., Nguyen, T.T., et al.Pyrido[2,3-d]pyrimidine angiotensin II antagonistsJ. Med. Chem.37(4)542-550(1994)
| Cas No. | 145733-36-4 | SDF | |
| 别名 | 他索沙坦,WAY-ANA 756 | ||
| Canonical SMILES | O=C1CCC2=C(C)N=C(C)N=C2N1CC3=CC=C(C4=CC=CC=C4C5=NNN=N5)C=C3 | ||
| 分子式 | C23H21N7O | 分子量 | 411.46 |
| 溶解度 | DMSO : 125 mg/mL (303.80 mM) | 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 | 2.4304 mL | 12.1518 mL | 24.3037 mL |
| 5 mM | 0.4861 mL | 2.4304 mL | 4.8607 mL |
| 10 mM | 0.243 mL | 1.2152 mL | 2.4304 mL |
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每只动物给药体积 | ul | |
动物数量 | 只 |
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Tasosartan, enoltasosartan, and angiotensin II receptor blockade: the confounding role of protein binding
J Pharmacol Exp Ther 2000 Nov;295(2):649-54.PMID:11046101doi
Tasosartan is a long-acting angiotensin II (AngII) receptor blocker. Its long duration of action has been attributed to its active metabolite enoltasosartan. In this study we evaluated the relative contribution of Tasosartan and enoltasosartan to the overall pharmacological effect of Tasosartan. AngII receptor blockade effect of single doses of Tasosartan (100 mg p.o. and 50 mg i.v) and enoltasosartan (2.5 mg i.v.) were compared in 12 healthy subjects in a randomized, double blind, three-period crossover study using two approaches: the in vivo blood pressure response to exogenous AngII and an ex vivo AngII radioreceptor assay. Tasosartan induced a rapid and sustained blockade of AngII subtype-1 (AT1) receptors. In vivo, Tasosartan (p.o. or i.v.) blocked by 80% AT1 receptors 1 to 2 h after drug administration and still had a 40% effect at 32 h. In vitro, the blockade was estimated to be 90% at 2 h and 20% at 32 h. In contrast, the blockade induced by enoltasosartan was markedly delayed and hardly reached 60 to 70% despite the i.v. administration and high plasma levels. In vitro, the AT1 antagonistic effect of enoltasosartan was markedly influenced by the presence of plasma proteins, leading to a decrease in its affinity for the receptor and a slower receptor association rate. The early effect of Tasosartan is due mainly to Tasosartan itself with little if any contribution of enoltasosartan. The antagonistic effect of enoltasosartan appears later. The delayed in vivo blockade effect observed for enoltasosartan appears to be due to a high and tight protein binding and a slow dissociation process from the carrier.
Effects of angiotensin antagonism with Tasosartan on regional and systemic haemodynamics in hypertensive patients
J Hypertens 1998 Dec;16(12 Pt 2):2085-9.PMID:9886901DOI:10.1097/00004872-199816121-00034.
Objective: Evaluate the effects of 2 weeks of treatment with Tasosartan (1) on cardiac function at rest and during submaximal exercise, (2) on exercise peak oxygen uptake, and (3) on regional haemodynamics at rest in a control condition and during the recovery period of submaximal exercise in patients with essential hypertension. Design and methods: Twenty-four patients with moderate hypertension participated in this randomized, double-blind, crossover, placebo-controlled study. Each patient received Tasosartan (100 mg/day) or placebo during two periods of 2 weeks separated by 2 weeks of washout. Ambulatory blood pressure was assessed at the end of each period. Blood pressure, heart rate, cardiac output, stroke volume, total peripheral resistance were measured at rest and during submaximal exercise at the same end points. Regional blood flow and vascular resistance were additionally assessed in the forearm and calf at rest. Results: At rest in the control condition, Tasosartan significantly reduced blood pressure although total peripheral resistance, cardiac output and stroke volume as well as forearm and calf vascular resistances were not significantly affected compared to placebo. During submaximal exercise and during the recovery period after submaximal exercise, the reduced blood pressure found with Tasosartan was associated with a reduced total peripheral resistance compared to placebo whereas cardiac output, heart rate, or stroke volume were not affected. Peak workload and oxygen uptake were unaffected by Tasosartan. Conclusions: The results of this study indicate that antagonism of the AT1 receptor with Tasosartan reduces blood pressure at rest and during submaximal exercise but not during maximal exercise. The reduced blood pressure was associated with a reduced total peripheral resistance during submaximal exercise but not at rest in the control condition while cardiac output was unaltered in either condition. Lastly, Tasosartan did not impair working capacity as measured from peak workload and oxygen uptake.
A pharmacokinetic and pharmacodynamic study of the potential drug interaction between Tasosartan and atenolol in patients with stage 1 and 2 essential hypertension
J Clin Pharmacol 2000 Mar;40(3):231-41.PMID:10709151DOI:10.1177/00912700022008892.
The primary objective of this study was to evaluate the pharmacokinetics (PK) and pharmacodynamics (PD) of Tasosartan and atenolol administered alone and concomitantly under steady-state conditions in 17 patients ages 18 to 65 years diagnosed with stage 1 to 2 essential hypertension. After a 3- to 14-day qualification period, all patients received placebo Tasosartan on days--1 through 5 and 25 through 34, atenolol alone (50 mg) on days 1 through 5, atenolol (50 mg) + Tasosartan (50 mg) on days 6 through 19, and Tasosartan (50 mg) alone on days 20 through 24. A PK and PD evaluation of atenolol alone was performed on study day 5. On study day 19, PK and PD of both Tasosartan and atenolol were assessed. PK and PD evaluation for Tasosartan alone was assessed on study day 24. The coadministration of atenolol + Tasosartan did not affect the pharmacokinetics of Tasosartan, its major metabolite (enoltasosartan), or atenolol when compared with Tasosartan or atenolol administered separately. For area under the change in diastolic blood pressure curve, the reduction was significantly greater after Tasosartan + atenolol compared with that after atenolol alone (336 +/- 85 and 190 +/- 71 mmHg.24 h; p < 0.05 for combination and atenolol alone, respectively; mean +/- SEM). Combination therapy also caused a maximal reduction in diastolic blood pressure that is significantly more than with monotherapy with atenolol (-27 +/- 2 mmHg and -20 +/- 2 mmHg, respectively, p < 0.05). The additive effects of Tasosartan and atenolol in decreasing diastolic blood pressure may provide a rationale for combination antihypertensive therapy.
Efficacy and tolerability of Tasosartan, a novel angiotensin II receptor blocker: results from a 10-week, double-blind, placebo-controlled, dose-titration study. Tasosartan Investigators Group
Am Heart J 1999 Jan;137(1):118-25.PMID:9878944DOI:10.1016/s0002-8703(99)70467-9.
Background: Angiotensin II receptor antagonists are selective blockers of the renin-angiotensin system and represent an alternative to angiotensin-converting enzyme inhibitors in the treatment of hypertension. Tasosartan is a newly developed nonpeptide AT1 receptor blocker. Methods and results: In this double-blind, randomized, dose-titration, multicenter trial, Tasosartan and placebo were compared in patients with stage I and stage II hypertension. A prequalification washout period (antihypertensive medications withdrawn) and a 2-week qualification period (patients received single-blind placebo) preceded a 10-week, double-blind treatment period. The patients received either 50 mg Tasosartan (n = 132) or placebo (n = 130) once per day and were evaluated once per week. The dose of Tasosartan was increased at 3-week intervals to 100 mg and then to 200 mg if the mean sitting diastolic blood pressure (SiDBP) exceeded 90 mm Hg. Compared with placebo, Tasosartan produced significantly (P <.05) greater reductions in both SiDBP (-9.4 +/- 0.7 vs -2.0 +/- 0.7 mm Hg) and sitting systolic blood pressure (SBP) (-12.2 +/- 1.2 vs +0.4 +/- 1.2 mm Hg). The rate of response (SiDBP /=10 mm Hg) was significantly (P <.05) greater in the Tasosartan group than in the placebo group (55% vs 19%). The mean 24-hour blood pressure reduction with Tasosartan was -12.6 +/- 0. 9/-8.1 +/- 0.6, significantly greater (P <.05) than the reduction with placebo (+0.6 +/- 0.9/+0.5 +/- 0.6 mm Hg). The trough-to-peak ratio (determined from the ambulatory data) was 0.66 for DBP and 0. 72 for SBP for the Tasosartan treatment group, demonstrating 24-hour efficacy with once-a-day administration. The safety profile of Tasosartan was similar to placebo. Conclusions: These results demonstrate that Tasosartan at 50 to 200 mg given once a day over a titration period of 10 weeks was effective and safe in the treatment of essential hypertension.
A randomized, double-blind, placebo-controlled, parallel-group, multicenter trial of four doses of Tasosartan in patients with essential hypertension. Tasosartan Investigator's Group
Am J Hypertens 1998 Apr;11(4 Pt 1):454-61.PMID:9607384DOI:10.1016/s0895-7061(97)00487-1.
Tasosartan, a new, long-acting, nonpeptide angiotensin II receptor antagonist was evaluated in a randomized, double-blind, placebo-controlled, multicenter trial at 21 sites in the United States and Canada. After a 2-week, placebo washout qualification period, 278 patients (187 men/91 women) with a mean age of 53.4+/-9.5 years (range, 30 to 70 years) and a baseline sitting diastolic blood pressure (DBP) of 95 to 114 mm Hg were randomly assigned to receive placebo (n = 56), or 10 mg (n = 57), 30 mg (n = 55), 100 mg (n = 55), or 300 mg (n = 55) Tasosartan for 4 weeks. The treatment period was followed by a 2-week washout period. Ambulatory blood pressure (BP) monitoring was performed at the end of the placebo washout period and after at least 4 weeks of double-blind treatment. Clinically significant placebo-adjusted differences in baseline sitting systolic blood pressure (SBP)/DBP were observed in the 10 mg (5/3 mm Hg), 30 mg (5/4 mm Hg), 100 mg (10/7 mm Hg) and 300 mg (10/7 mm Hg) dose groups (P < .05). A dose-response relationship (P < .001) was observed within 1 to 2 weeks of treatment initiation and was maintained throughout the double-blind period. Discontinuation of Tasosartan therapy was not associated with rebound hypertension. Moreover, significant (P < .05) placebo-adjusted differences in ambulatory SBP/DBP and a significant dose-response relationship (P < .001) were observed with all Tasosartan dosages during the 24-h, daytime, and nighttime periods. Placebo-adjusted trough-to-peak ratios ranged from 87% to 100% for ambulatory SBP and 64% to 81% for DBP. In general, no significant differences were observed between the Tasosartan treatment groups and the placebo group in the incidence of adverse events. Headache incidence was significantly lower in the 300 mg dose group than the placebo group. In conclusion, Tasosartan at dosages of 10, 30, 100, or 300 mg given once daily produced a significant and dose-related reduction in both clinic and ambulatory BP that was maintained over the 24-h period. Tasosartan was generally well tolerated.