规格 | 价格 | 库存 | 数量 |
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100mg |
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250mg |
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500mg |
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1g |
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Other Sizes |
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靶点 |
binding of [125I]-angiotensin II to VSMC ( IC50 = 1.1 nM )
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体外研究 (In Vitro) |
Losartan Carboxylic Acid (E-3174) 可抑制 [125I]-血管紧张素 II 与 VSMC 的特异性结合,IC50 为 1.1 nM。 Losartan Carboxylic Acid 可消除血管紧张素 II 诱导的 VSMC 中肌醇磷酸的形成。 Losartan Carboxylic Acid 抑制血管紧张素 II 诱导的细胞内 Ca2+ 浓度升高,IC50 为 5 nM。氯沙坦羧酸在阻断血管紧张素 II 诱导的 Egr-1 mRNA 增加方面比氯沙坦更有效。 Losartan Carboxylic Acid 抑制血管紧张素 II 诱导的细胞蛋白合成,IC50 为 3 nM[1]。
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体内研究 (In Vivo) |
Losartan Carboxylic Acid (E-3174)(0.1 mg/kg;静脉注射,然后 0.02 mg/kg/h,持续 5.5 小时)对血管紧张素 I 的升压反应产生相似水平的抑制 (87±4%) [3]。静脉注射氯沙坦羧酸(0.1 mg/kg+0.01 mg/kg/min)给最近(8.1±0.4天)前壁心肌梗死的麻醉犬。治疗开始后 1 小时开始对左回旋支冠状动脉进行电解损伤,以诱导血栓闭塞和后外侧缺血[4]。动物模型: 任意性别的杂种狗,体重 15-25 kg[3] 剂量: 0.1 mg/kg(随后 0.02 mg/kg/h) 给药: 静脉注射 5.5 小时 结果: 升压反应降低 87±4 %。
氯沙坦、EXP3174和卡托普利提高了血浆肾素活性,并相对显著地降低了平均动脉压。任何治疗均未发现明显的心电图或心脏电生理效应。急性后外侧缺血诱发致死性心律失常的发生率为:溶媒7/9(77%);氯沙坦6/8(75%);EXP3174,2/8(25%;与对照组相比,p<0.05);卡托普利7/10(70%)。急性后外侧缺血发作的时间或潜在的前梗死面积在组间没有差异。 结论:EXP3174可降低致死性缺血性室性心律失常的发生率,但氯沙坦和卡托普利均不能。EXP3174的抗心律失常功效可能是由于急性心肌缺血期间形成的局部心脏AII的有害作用减弱,或者是EXP3174特有的非AII相关活性。这些发现表明,在人类中,氯沙坦代谢转化为EXP3174可能提供抗心律失常保护[4]。 |
酶活实验 |
研究了KRH-594(一种新的血管紧张素II(AII)1型(AT1)受体选择性拮抗剂)与大鼠肝膜和重组AT1和AT2受体的结合特性。当预孵育时间为1-2小时时,用KRH-594预孵育大鼠肝膜对[125I]-AII结合的抑制作用最大。用KRH-592预孵育2小时降低了B(max)值,增加了Kd值。对于人AT1、人AT2、大鼠AT1A和大鼠AT1B受体,KRH-594的Ki值分别为1.24、9360、0.67和1.02 nm。人AT1受体K1值的排序为KRH-594>>EXP3174>坎地沙坦=AII。人AT1和AT2受体的特异性顺序为坎地沙坦>EXP3174>KRH-594。尽管人AT2受体与KRH-594(30微M)或CGP 42112(选择性AT2受体拮抗剂;0.3 nM)预孵育2小时可抑制[125I]-AII的结合,但KRH-594的抑制作用并不显著。这些结果表明,KRH-594以一种无法克服的方式与AT1受体结合,在非常高的剂量(30微M)下,它也可能以一种可以克服的方式结合AT2受体[2]。
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细胞实验 |
目的:EXP3174是氯沙坦(原名DuP753)的代谢产物,氯沙坦是一种非肽类血管紧张素II受体拮抗剂。
设计:研究这两种拮抗剂对血管紧张素II诱导的血管平滑肌细胞(VSMC)反应的抑制作用。
方法:通过[3H]-胸苷掺入细胞DNA和细胞蛋白测量来确定血管紧张素II对细胞生长的影响。用fura-2法测定细胞内胞浆Ca2+浓度。用肌醇标记细胞后,通过高效液相色谱法测定肌醇磷酸酯。通过Northern印迹法测定早期生长反应基因-1(Egr-1)信使RNA(mRNA)的表达。使用[125I]-血管紧张素II进行拮抗剂的结合和置换研究。
结果:[125I]-血管紧张素II的表观解离常数(Kd)为5.9 nmol/l(最大结合系数为69 fmol/10(6)细胞)。氯沙坦、EXP3174和沙拉酶抑制[125I]-血管紧张素II与VSMC的特异性结合,其半最大抑制浓度(IC50)分别为1.0 X 10(-8)、1.1 X 10(-9)和1.8 X 10(-9)mol/l。EXP3174和氯沙坦消除了血管紧张素II诱导的VSMC中肌醇磷酸的形成。EXP3174和氯沙坦抑制了血管紧张素II诱导的细胞内胞浆Ca2+浓度的升高,IC50分别为5 X 10(-9)和5 X 10(-8)mol/l。EXP3174在阻断血管紧张素II诱导的Egr-1 mRNA增加方面比氯沙坦更有效。EXP3174和氯沙坦分别以3 X 10(-9)和4 X 10(-8)mol/l的IC50抑制血管紧张素Ⅱ诱导的细胞蛋白质合成。
结论:这些结果表明,EXP3174在阻断血管紧张素II诱导的细胞反应方面明显优于氯沙坦[1]。
在存在或不存在推荐剂量的氯沙坦的情况下,用 15% FBS 或 Ang II 处理细胞 48 小时。使用MTT测定法评估细胞增殖。 |
动物实验 |
Mongrel dogs of either sex, weighing 15-25 kg
0.1 mg/kg (followed by 0.02 mg/kg/h) i.v. for 5.5 hours 1. In order to determine whether the renin-angiotensin system is involved in myocardial ischaemia-reperfusion injury, we investigated and compared the effects on infarct size of two different drugs which interfere with this system, i.e., an angiotensin II (AT1) antagonist, EXP3174, and an angiotensin I-converting enzyme inhibitor (ACEI), enalaprilat in a canine model of ischaemia-reperfusion. 2. EXP3174 (0.1 mg kg-1, i.v. followed by 0.02 mg kg-1 h-1 for 5.5 h) and enalaprilate (0.3 mg kg-1, i.v. followed by 0.06 mg kg-1 h-1 for 5.5 h) were used in doses inducing a similar level of inhibition (87 +/- 4 and 91 +/- 3%, respectively) of the pressor responses to angiotensin I. Control animals received saline. 3. Infarct size and area at risk were quantified by ex vivo dual coronary perfusion with triphenyltetrazolium chloride and monastral blue dye. Regional myocardial blood flows (ischaemic and nonischaemic, endocardial, epicardial) were assessed by the radioactive microsphere technique. 4. Both EXP3174 and enalaprilat induced a decrease in mean arterial blood pressure. However, non significant changes in regional myocardial blood flows, whether ischaemic or nonischaemic, were observed after administration of either the ACEI or the AT1 antagonist. 5. The size of the area at risk was similar in the three groups. By direct comparison, there were no significant differences between infarct sizes in the three groups. Furthermore, there was a close inverse relationship between infarct size and transmural mean collateral blood flow in controls, and none of the treatments altered this correlation. Thus, neither EXP3174 nor enalaprilat limited infarct size. 6. These results indicate that activation of the renin-angiotensin system does not contribute to myocyte death in this canine ischaemia/reperfusion model.[3] Intravenous losartan (1 mg/kg + 0.03 mg/kg/min), EXP3174 (0.1 mg/kg + 0.01 mg/kg/min), captopril (1 mg/kg + 0.5 mg/kg/h) or vehicle were infused in anesthetized dogs with recent (8.1 +/- 0.4 days) anterior myocardial infarction. Electrolytic injury of the left circumflex coronary artery to induce thrombotic occlusion and posterolateral ischemia was initiated 1 h after the start of treatment.[4] |
药代性质 (ADME/PK) |
Metabolism / Metabolites
Losartan carboxylic acid is a known human metabolite of losartan carboxaldehyde and losartan. |
毒性/毒理 (Toxicokinetics/TK) |
mouse LD50 intraperitoneal 441 mg/kg SENSE ORGANS AND SPECIAL SENSES: MYDRIASIS (PUPILLARY DILATION): EYE; BEHAVIORAL: TREMOR; LUNGS, THORAX, OR RESPIRATION: RESPIRATORY DEPRESSION Kiso to Rinsho. Clinical Report., 28(3959), 1994
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参考文献 |
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其他信息 |
Losartan carboxylic acid is a biphenylyltetrazole that is losartan with the hydroxymethyl group at position 5 on the imidazole ring replaced with a carboxylic acid. It has a role as a metabolite. It is a biphenylyltetrazole, a member of imidazoles and an organochlorine compound. It is functionally related to a losartan.
The antiarrhythmic efficacies of the competitive angiotensin II (AII) antagonist losartan, losartan's more potent noncompetitive AII antagonist human metabolite EXP3174 and the angiotensin-converting enzyme inhibitor captopril were assessed in a canine model of recent myocardial infarction. Background: Multiple hemodynamic and electrophysiologic effects of AII may contribute to cardiac electrical instability. In the recent Losartan Heart Failure Study, Evaluation of Losartan in the Elderly (ELITE), a 722-patient trial primarily designed to assess effects on renal function, an unexpected survival benefit was observed with losartan compared with captopril, with the lower mortality using losartan primarily confined to a reduction in sudden cardiac death.[4] |
分子式 |
C22H21CLN6O2
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分子量 |
436.89
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精确质量 |
436.14
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元素分析 |
C, 60.48; H, 4.85; Cl, 8.11; N, 19.24; O, 7.32
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CAS号 |
124750-92-1
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相关CAS号 |
Losartan-d4 (carboxylic acid); 1246820-62-1; Losartan; 114798-26-4; Losartan potassium; 124750-99-8; Losartan carboxylic acid-d4 hydrochloride
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PubChem CID |
108185
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外观&性状 |
White to off-white solid powder
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LogP |
5
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tPSA |
110
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氢键供体(HBD)数目 |
2
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氢键受体(HBA)数目 |
6
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可旋转键数目(RBC) |
8
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重原子数目 |
31
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分子复杂度/Complexity |
590
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定义原子立体中心数目 |
0
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InChi Key |
ZEUXAIYYDDCIRX-UHFFFAOYSA-N
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InChi Code |
InChI=1S/C22H21ClN6O2/c1-2-3-8-18-24-20(23)19(22(30)31)29(18)13-14-9-11-15(12-10-14)16-6-4-5-7-17(16)21-25-27-28-26-21/h4-7,9-12H,2-3,8,13H2,1H3,(H,30,31)(H,25,26,27,28)
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化学名 |
2-butyl-5-chloro-3-[[4-[2-(2H-tetrazol-5-yl)phenyl]phenyl]methyl]imidazole-4-carboxylic acid
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别名 |
Losartan Carboxylic Acid; EXP 3174; Losartan carboxylic acid; 124750-92-1; EXP-3174; Exp3174; EXP 3174; E-3174; Carboxylosartan; 2-butyl-5-chloro-3-[[4-[2-(2H-tetrazol-5-yl)phenyl]phenyl]methyl]imidazole-4-carboxylic acid; EXP-3174; EXP3174; E3174; E-3174; E 3174
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HS Tariff Code |
2934.99.9001
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存储方式 |
Powder -20°C 3 years 4°C 2 years In solvent -80°C 6 months -20°C 1 month |
运输条件 |
Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)
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溶解度 (体外实验) |
DMSO: ~87 mg/mL (~199.1 mM)
Ethanol: ~87 mg/mL |
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溶解度 (体内实验) |
配方 1 中的溶解度: ≥ 2.08 mg/mL (4.76 mM) (饱和度未知) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (这些助溶剂从左到右依次添加,逐一添加), 澄清溶液。
例如,若需制备1 mL的工作液,可将100 μL 20.8 mg/mL澄清DMSO储备液加入400 μL PEG300中,混匀;然后向上述溶液中加入50 μL Tween-80,混匀;加入450 μL生理盐水定容至1 mL。 *生理盐水的制备:将 0.9 g 氯化钠溶解在 100 mL ddH₂O中,得到澄清溶液。 配方 2 中的溶解度: ≥ 2.08 mg/mL (4.76 mM) (饱和度未知) in 10% DMSO + 90% Corn Oil (这些助溶剂从左到右依次添加,逐一添加), 澄清溶液。 例如,若需制备1 mL的工作液,可将 100 μL 20.8 mg/mL 澄清 DMSO 储备液加入到 900 μL 玉米油中并混合均匀。 请根据您的实验动物和给药方式选择适当的溶解配方/方案: 1、请先配制澄清的储备液(如:用DMSO配置50 或 100 mg/mL母液(储备液)); 2、取适量母液,按从左到右的顺序依次添加助溶剂,澄清后再加入下一助溶剂。以 下列配方为例说明 (注意此配方只用于说明,并不一定代表此产品 的实际溶解配方): 10% DMSO → 40% PEG300 → 5% Tween-80 → 45% ddH2O (或 saline); 假设最终工作液的体积为 1 mL, 浓度为5 mg/mL: 取 100 μL 50 mg/mL 的澄清 DMSO 储备液加到 400 μL PEG300 中,混合均匀/澄清;向上述体系中加入50 μL Tween-80,混合均匀/澄清;然后继续加入450 μL ddH2O (或 saline)定容至 1 mL; 3、溶剂前显示的百分比是指该溶剂在最终溶液/工作液中的体积所占比例; 4、 如产品在配制过程中出现沉淀/析出,可通过加热(≤50℃)或超声的方式助溶; 5、为保证最佳实验结果,工作液请现配现用! 6、如不确定怎么将母液配置成体内动物实验的工作液,请查看说明书或联系我们; 7、 以上所有助溶剂都可在 Invivochem.cn网站购买。 |
制备储备液 | 1 mg | 5 mg | 10 mg | |
1 mM | 2.2889 mL | 11.4445 mL | 22.8891 mL | |
5 mM | 0.4578 mL | 2.2889 mL | 4.5778 mL | |
10 mM | 0.2289 mL | 1.1445 mL | 2.2889 mL |
1、根据实验需要选择合适的溶剂配制储备液 (母液):对于大多数产品,InvivoChem推荐用DMSO配置母液 (比如:5、10、20mM或者10、20、50 mg/mL浓度),个别水溶性高的产品可直接溶于水。产品在DMSO 、水或其他溶剂中的具体溶解度详见上”溶解度 (体外)”部分;
2、如果您找不到您想要的溶解度信息,或者很难将产品溶解在溶液中,请联系我们;
3、建议使用下列计算器进行相关计算(摩尔浓度计算器、稀释计算器、分子量计算器、重组计算器等);
4、母液配好之后,将其分装到常规用量,并储存在-20°C或-80°C,尽量减少反复冻融循环。
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)。如该浓度超过该批次药物DMSO溶解度,请首先与我们联系。
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 ddH2O,混匀澄清。
(1) 请确保溶液澄清之后,再加入下一种溶剂 (助溶剂) 。可利用涡旋、超声或水浴加热等方法助溶;
(2) 一定要按顺序加入溶剂 (助溶剂) 。
NCT Number | Recruitment | interventions | Conditions | Sponsor/Collaborators | Start Date | Phases |
NCT03864042 | Active Recruiting |
Drug: dextromethorphan Drug: losartan |
Advanced Solid Tumors Metastatic Melanoma |
Pfizer | January 2, 2018 | Phase 1 |
NCT01797926 | Completed | Drug: Reference Treatment: 5 mg amlodipine + 50 mg losartan Drug: Reference Treatment:5 mg amlodipine + 100 mg losartan |
Hypertension | GlaxoSmithKline | May 23, 2013 | Phase 1 |
NCT01033318 | Completed | Drug: MK1809 Drug: Comparator: Losartan Drug: Comparator: Placebo |
Hypertension | Merck Sharp & Dohme LLC | September 11, 2007 | Phase 1 |
NCT01713647 | Completed | Drug: Amlodipin, losartan, HCTZ | Fasting | Pharmaceutical Research Unit, Jordan |
October 2012 | Phase 1 |
NCT01766050 | Completed | Drug: Losartan Drug: Caffeine |
Transplant Rejection | Bristol-Myers Squibb | January 2013 | Phase 4 |
Survival of losartan (n = 8; 1 mg/kg IV bolus + 0.03 mg/kg/min continuous IV infusion), EXP3174 (n = 8; 0.1 mg/kg IV bolus + 0.01 mg/kg/min continuous IV infusion), captopril (n = 10; 1 mg/kg IV bolus + 0.5 mg/kg/h continuous IV infusion) and vehicle-treated (n = 9) dogs with previous anterior myocardial infarction expressed as a function of time after onset of thrombotically induced acute posterolateral myocardial ischemia. J Am Coll Cardiol . 1999 Sep;34(3):876-84. td> |