Darusentan
(Synonyms: 达卢生坦,Lu-135252) 目录号 : GC35811
An ETA receptor antagonist
Cas No.:171714-84-4
Sample solution is provided at 25 µL, 10mM.
;)
,-1-7$$$37316672.jpg');)
;)
;)
$$$36806353.jpg');)
;33(7)%EF%BC%9A546-561$$$37156877.jpg');)
;)
;)
;)
%201124-1138.$$$35908550.jpg');)
%20766-780.$$$37100057.jpg');)
%20418-432.$$$36893736.jpg');)
%EF%BC%9A-240-255.$$$35108512.jpg');)
533-545$$$36543525.jpg');)
%201-13.$$$36600053.jpg');)
;)
Quality Control & SDS
- View current batch:
- Purity: >98.50%
- COA (Certificate Of Analysis)
- SDS (Safety Data Sheet)
- Datasheet
Darusentan is an endothelin type A (ETA) receptor antagonist (Ki = 13 nM in rat aortic vascular smooth muscle cells).1 It inhibits contractions induced by human endothelin-1 in isolated rat aortic rings and mesenteric microvessels with pA2 values of 8.1 and 7.97, respectively. Darusentan (50 mg/kg) decreases systolic blood pressure in DOCA-salt hypertensive rats, as well as reduces mean arterial pressure (MAP) and left ventricular developed pressure (LVDP) in normotensive pigs when administered at doses of 1 and 5 mg/kg.2,3 It reduces myocardial infarct size as a percentage of the area at risk in a porcine model of ischemia-reperfusion injury induced by ligation of the left anterior descending (LAD) coronary artery.3
1.Liang, F., Glascock, C.B., Schafer, D.L., et al.Darusentan is a potent inhibitor of endothelin signaling and function in both large and small arteriesCan. J. Physiol. Pharmacol.88(8)840-849(2010) 2.Schiffrin, E.L., Turgeon, A., and Deng, L.Y.Effect of chronic ETA-selective endothelin receptor antagonism on blood pressure in experimental and genetic hypertension in ratsBr. J. Pharmacol.121(5)935-940(1997) 3.Gonon, A.T., Wang, Q.D., Shimizu, M., et al.The novel non-peptide selective endothelin A receptor antagonist LU 135 252 protects against myocardial ischaemic and reperfusion injury in the pigActa Physiol. Scand.163(2)131-137(1998)
| Cas No. | 171714-84-4 | SDF | |
| 别名 | 达卢生坦,Lu-135252 | ||
| Canonical SMILES | COC1=NC(O[C@H](C(O)=O)C(C2=CC=CC=C2)(C3=CC=CC=C3)OC)=NC(OC)=C1 | ||
| 分子式 | C22H22N2O6 | 分子量 | 410.42 |
| 溶解度 | DMSO: ≥ 125 mg/mL (304.57 mM); Water: < 0.1 mg/mL (insoluble) | 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。 |
||
| Shipping Condition | 评估样品解决方案：配备蓝冰进行发货。所有其他可用尺寸：配备RT，或根据请求配备蓝冰。 | ||
| 制备储备液 | |||
 |
1 mg | 5 mg | 10 mg |
| 1 mM | 2.4365 mL | 12.1826 mL | 24.3653 mL |
| 5 mM | 0.4873 mL | 2.4365 mL | 4.8731 mL |
| 10 mM | 0.2437 mL | 1.2183 mL | 2.4365 mL |
| 第一步：请输入基本实验信息（考虑到实验过程中的损耗，建议多配一只动物的药量） | ||||||||||
| 给药剂量 | mg/kg |  |
动物平均体重 | g | |
每只动物给药体积 | ul | |
动物数量 | 只 |
| 第二步：请输入动物体内配方组成（配方适用于不溶于水的药物；不同批次药物配方比例不同，请联系GLPBIO为您提供正确的澄清溶液配方） | ||||||||||
| % DMSO % % Tween 80 % saline | ||||||||||
| 计算重置 | ||||||||||
计算结果:
工作液浓度： mg/ml；
DMSO母液配制方法： mg 药物溶于 μL DMSO溶液（母液浓度 mg/mL，
体内配方配制方法：取 μL DMSO母液，加入 μL PEG300，混匀澄清后加入μL Tween 80，混匀澄清后加入 μL saline，混匀澄清。
1. 首先保证母液是澄清的；
2.
一定要按照顺序依次将溶剂加入，进行下一步操作之前必须保证上一步操作得到的是澄清的溶液，可采用涡旋、超声或水浴加热等物理方法助溶。
3. 以上所有助溶剂都可在 GlpBio 网站选购。
Darusentan: a new perspective for treatment of resistant hypertension?
Expert Opin Investig Drugs 2008 Aug;17(8):1255-63.PMID:18616421DOI:10.1517/13543784.17.8.1255.
Despite multi-drug therapy, hypertension remains uncontrolled in a significant amount of patients, especially those with multiple cardiovascular risk factors. Endothelin-1 is a long lasting and very potent vasoconstrictor and plays a key role in cardiovascular hemostasis. Endothelin mediates its biological activity in humans through the endothelin A and B receptors. The selective endothelin--A receptor antagonist Darusentan may be a new treatment option in patients with resistant hypertension. The objectives were that the clinical experience and the evidence for therapy with Darusentan in resistant systemic hypertension were reviewed. The methods by the authors were that the leading journals which publish basic science and clinical research in the area of cardiovascular diseases and PubMed were scanned. In conclusion, early clinical results from Phase II studies suggest that Darusentan may find a place in the treatment of resistant hypertension.
Darusentan, a selective endothelin A receptor antagonist, for the oral treatment of resistant hypertension
Ther Adv Cardiovasc Dis 2010 Aug;4(4):231-40.PMID:20660536DOI:10.1177/1753944710373785.
Resistant hypertension is defined as failure to lower blood pressure to target when a patient adheres to the maximum tolerated doses of three antihypertensive drugs including a diuretic. Notwithstanding the wide availability of several antihypertensive agents and the continued recommendation of dietary and lifestyle modifications, the prevalence of resistant hypertension remains high and is expected to increase thus underscoring the need for potential new treatment modalities in resistant hypertension. Endothelin-1 is a long-lasting potent vasoconstrictor and plays a key role in cardiovascular haemostasis. Endothelin mediates its biological activity in humans through the endothelin A and B receptors. The clinical experience and the evidence for therapy with Darusentan in resistant systemic hypertension are reviewed. The leading journals that publish basic science and clinical research in the area of cardiovascular diseases and PubMed were scanned. While results from early clinical studies suggested that Darusentan might emerge as new treatment option in patients with resistant hypertension, results from recent studies suggests that Darusentan appears unlikely to find its way in the armamentarium for treatment of resistant hypertension.
Darusentan is a potent inhibitor of endothelin signaling and function in both large and small arteries
Can J Physiol Pharmacol 2010 Aug;88(8):840-9.PMID:20725142DOI:10.1139/Y10-061.
Endothelin is a potent vasoconstrictor often up-regulated in hypertension. Endothelin vasoconstriction is mediated via the G-protein coupled endothelin A (ETA) receptor present on vascular smooth muscle. Endothelin receptor antagonists (ERAs) have been shown to antagonize ET-induced vasoconstriction. We describe the primary pharmacology of Darusentan, a propanoic acid based ERA currently in phase 3 clinical trials for resistant hypertension. Darusentan was tested in membrane-, cell-, and tissue-based assays to determine its biochemical and functional potency. Rat aortic vascular smooth muscle cells (RAVSMs) were characterized using flow cytometry. RAVSM membrane fractions tested in saturation experiments exhibited moderate endothelin receptor density. Receptor counting revealed that >95% of the endothelin receptors in these fractions were the ETA subtype. (S)-Darusentan competed for radiolabeled endothelin binding in RAVSM membranes with single-site kinetics, exhibiting a Ki = 13 nmol/L. (R)-Darusentan exhibited no binding activity. In cultured RAVSMs, endothelin induced increases in inositol phosphate and Ca2+ signaling, both of which were attenuated by (S)-darusentan in a concentration-dependent manner. In isolated endothelium-denuded rat aortic rings, (S)-darusentan inhibited endothelin-induced vascular contractility with a pA2 = 8.1 +/- 0.14 (n = 4 animals; mean +/- SD). (R)-Darusentan had no effect. The vasorelaxant potency of (S)-darusentan did not change when determined in isolated denuded rat mesenteric arterioles, suggesting a similar mode of action in both conductance and resistance arteries. In vascular smooth muscle, (S)-darusentan is an ERA with high affinity for the ET receptor, which in this preparation is predominantly ETA receptors. (S)-Darusentan inhibits endothelin-induced signaling related to pro-contractile activity and is a potent inhibitor of vasoconstriction in large and small arteries.
Darusentan: an effective endothelinA receptor antagonist for treatment of hypertension
Am J Hypertens 2002 Jul;15(7 Pt 1):583-9.PMID:12118903DOI:10.1016/s0895-7061(02)02933-3.
Background: The antihypertensive efficacy and safety of Darusentan, a new selective endothelin, antagonist was investigated. Methods: In a multicenter randomized, double-blind, parallel-group, dose-response study, a 2-week placebo run-in period was followed by a 6-week treatment period and then a 2-week placebo withdrawal period. At baseline before Darusentan therapy, the average blood pressure (BP) of the patient population studied was diastolic 103.49 (SD 3.55) and systolic 168.27 (SD 16.63) mm Hg. In total, 392 patients were randomized (Darusentan 10 mg: 94 patients, 30 mg: 103 patients, 100 mg: 96 patients, placebo: 99 patients). Results: Darusentan significantly reduced diastolic (mean difference to placebo: 10 mg: -3.7 mm Hg, 95% confidence interval (CI): -6.6, -0.9, P = .009; 30 mg: -4.9 mm Hg, 95% CI: -7.7, -2.2, P = .0005; 100 mg: -8.3 mm Hg, 95% CI: -11.1, -5.5, P = .0001) and systolic BP (mean difference to placebo: 10 mg: -6.0 mm Hg, 95% CI: -11.0, -0.9, P = .02; 30 mg: -7.3 mm Hg, 95% CI: - 12.3, -2.4, P = .004; 100 mg: - 11.3 mm Hg, 95% CI: -16.3, -6.2, P = .0001). Pulse rate remained unchanged in all groups. There was a trend toward more adverse events in the active treatment groups (placebo: 30.3%, 10 mg: 44.7%, 30 mg: 40.8%, 100 mg: 49.0%). Headache was the most commonly reported adverse event, with no relevant difference among treatments. Flushing and peripheral edema were seen in a dose-dependent fashion in the active treatment groups only. Conclusion: These data, the first, suggest the therapeutic benefit of selective endothelinA receptor antagonism in human hypertension.
Darusentan (Abbott Laboratories)
IDrugs 2001 Nov;4(11):1284-92.PMID:15942834doi
Abbott (formerly Knoll) is developing Darusentan, an endothelin A antagonist, as a potential treatment for congestive heart failure (CHF) [398274]. The compound entered phase II trials in December 1998 [310187]. In a model of monocrotaline-induced pulmonary hypertension, Darusentan (50 mg/kg/day), significantly reduced right ventricular systolic pressure, and in a canine model of CHF chronic treatment for 2 weeks significantly reduced left ventricular end diastolic pressure, mean pulmonary artery pressure, and right atrial pressure. Darusentan is a selective antagonist in vitro (ET(A): K(i) = 1.4 nM; ET(B): K(i) = 184 nM) [339872].