Lixivaptan (VPA-985) |
| Catalog No.: GC32453 |
Lixivaptan (VPA-985) (VPA-985, WAY-VPA 985) is an orally active and selective vasopressin receptor V2 antagonist, with IC50 values of 1.2 and 2.3 nM for human and rat V2, respectively.
Sample solution is provided at 25 µL, 10mM.
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Purity: >99.50%
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Lixivaptan (VPA-985, WAY-VPA 985) is an orally active and selective vasopressin receptor V2 antagonist, with IC50 values of 1.2 and 2.3 nM for human and rat V2, respectively.
Lixivaptan displays competitive antagonist activity at V2 receptors[1].
In conscious dogs, water-loaded with 30 mL/kg (po) and arginine vasopressin (AVP)-treated (0.4 µg/kg in oil, sc), lixivaptan (1, 3, and 10 mg/kg po) increases Uvol over the AVP-treated vehicle group by 438, 1018, and 1133%, respectively, while Uosm decreases from 1222 mOsm/kg (water-loaded and AVP treated vehicle) to 307, 221, and 175 mOsm/kg, respectively. In homozygous Brattleboro rats lacking AVP, lixivaptan at 10 mg/kg po (i.e., 10 times the dose producing V2 antagonist activity) b.i.d. for 5 days, shows a sustained antagonist action without evidence of agonist effects. In a randomized double-blind placebo-controlled ascending single dose study, patients (deprived of fluids overnight before dosing) are dosed orally with 30, 75, or 150 mg of lixivaptan. All three doses increase urine flow and serum sodium concentrations and produced significant dose-related decreases in urinary osmolality[1]. Phase II clinical trials in patients with congestive heart failure, liver cirrhosis with ascites or syndrome of inappropriate antidiuretic hormone have demonstrated that lixivaptan increases water clearance without affecting renal sodium excretion or activating the neurohormonal system[2].
[1]. Albright JD, et al. 5-Fluoro-2-methyl-N-[4-(5H-pyrrolo[2,1-c]-[1, 4]benzodiazepin-10(11H)-ylcarbonyl)-3-chlorophenyl]benzamide (VPA-985): an orally active arginine vasopressin antagonist with selectivity for V2 receptors. J Med Chem. 1998 Jul 2;41(14):2442-4. [2]. Ghali JK, et al. Lixivaptan, a non-peptide vasopressin V2 receptor antagonist for the potential oral treatment of hyponatremia. IDrugs. 2010 Nov;13(11):782-92.
| Cas No. | 168079-32-1 | SDF | |
| Canonical SMILES | O=C(C1=C(Cl)C=C(NC(C2=CC(F)=CC=C2C)=O)C=C1)N(C3)C4=CC=CC=C4CN5C3=CC=C5 | ||
| Formula | C27H21ClFN3O2 | M.Wt | 473.93 |
| Solubility | DMSO : ≥ 150 mg/mL (316.50 mM) | Storage | 4°C, protect from light |
| General tips | For obtaining a higher solubility , please warm the tube at 37 ℃ and shake it in the ultrasonic bath for a while.Stock solution can be stored below -20℃ for several months. | ||
| Shipping Condition | Evaluation sample solution : ship with blue ice All other available size: ship with RT , or blue ice upon request |
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Hyponatremia in Heart Failure: Pathogenesis and Management
Curr Cardiol Rev 2019;15(4):252-261.PMID:30843491DOI:10.2174/1573403X15666190306111812.
Hyponatremia is a very common electrolyte abnormality, associated with poor short- and long-term outcomes in patients with heart failure (HF). Two opposite processes can result in hyponatremia in this setting: Volume overload with dilutional hypervolemic hyponatremia from congestion, and hypovolemic hyponatremia from excessive use of natriuretics. These two conditions require different therapeutic approaches. While sodium in the form of normal saline can be lifesaving in the second case, the same treatment would exacerbate hyponatremia in the first case. Hypervolemic hyponatremia in HF patients is multifactorial and occurs mainly due to the persistent release of arginine vasopressin (AVP) in the setting of ineffective renal perfusion secondary to low cardiac output. Fluid restriction and loop diuretics remain mainstay treatments for hypervolemic/ dilutional hyponatremia in patients with HF. In recent years, a few strategies, such as AVP antagonists (Tolvaptan, Conivaptan, and Lixivaptan), and hypertonic saline in addition to loop diuretics, have been proposed as potentially promising treatment options for this condition. This review aimed to summarize the current literature on pathogenesis and management of hyponatremia in patients with HF.
Lixivaptan, a non-peptide vasopressin V2 receptor antagonist for the potential oral treatment of hyponatremia
IDrugs 2010 Nov;13(11):782-92.PMID:21046526doi
Lixivaptan (VPA-985), being developed by Biogen Idec and Cardiokine, under license from Wyeth (now part of Pfizer), is a non-peptide, selective vasopressin V2 receptor antagonist for the potential oral treatment of hyponatremia associated with heart failure. Arginine vasopressin, the native V2 receptor ligand, stimulates water reabsorption via activation of V2 receptors that are expressed in the collecting ducts of the kidney. In preclinical studies, lixivaptan displayed competitive antagonist activity at V2 receptors in vitro, and increased urine volume and decreased urine osmolality in rats and dogs. The therapeutic benefits of lixivaptan are being evaluated in patients with conditions that are associated with water excess and hyponatremia. Phase II clinical trials in patients with congestive heart failure, liver cirrhosis with ascites or syndrome of inappropriate antidiuretic hormone have demonstrated that, unlike traditional diuretics, lixivaptan increases water clearance without affecting renal sodium excretion or activating the neurohormonal system. Administration of lixivaptan in combination with the diuretic furosemide has been tested in rats as well as in trials in healthy volunteers, in which the two agents were well tolerated. Ongoing phase III trials will determine the role of lixivaptan in the management of hyponatremia, especially when associated with heart failure.
Treatment of hyponatremia: the role of Lixivaptan
Expert Rev Clin Pharmacol 2014 Jul;7(4):431-41.PMID:24766294DOI:10.1586/17512433.2014.911085.
Hyponatremia is the most common electrolyte disorder and is associated with serious neurologic sequelae and increased mortality. Conventional treatment options for hyponatremia, such as fluid restriction, hypertonic saline, loop diuretics, demeclocycline or urea, are ineffective in the long-term. The present review considers the role of vasopressin receptor inhibitors (vaptans), focusing on Lixivaptan, in the treatment of patients with euvolemic or hypervolemic hyponatremia. Lixivaptan is an oral selective V2 receptor inhibitor, which produces a significantly greater increase of serum sodium levels compared with placebo. These effects seem promising, but more trials are needed to examine whether the beneficial effect of Lixivaptan on serum sodium concentration translates into clinical benefit in these patient populations.
The potential role for Lixivaptan in heart failure and in hyponatremia
Expert Opin Investig Drugs 2011 Jun;20(6):831-48.PMID:21548825DOI:10.1517/13543784.2011.579102.
Introduction: Hypervolemia and hyponatremia are common features in heart failure and have been associated with increased morbidity and mortality. Stimulation of arginine vasopressin (AVP) plays an important role in the development of both hypervolemia and hyponatremia. Lixivaptan is a selective vasopressin type 2 (V(2)) receptor antagonist that has been demonstrated to have the ability to induce aquaresis, the electrolyte sparing excretion of water, resulting in fluid removal as well as correction of hyponatremia. Areas covered: This article describes the prevalence, pathophysiology and current treatment limitations of hyponatremia, highlights the importance of arginine vasopressin and the potential role of arginine vasopressin antagonists and reviews all available literature on Lixivaptan, a selective V(2) receptor antagonist. Expert opinion: The available experience of Lixivaptan in heart failure, although limited, is encouraging. Its aquaretic effect provides the basis for its use to correct hypervolemia and hyponatremia in patients with heart failure, and the absence of neurhormonal stimulation provides positive signal for the exploration of its potential in improving outcomes.
Lixivaptan: a novel vasopressin receptor antagonist
Expert Opin Investig Drugs 2009 May;18(5):657-62.PMID:19379124DOI:10.1517/13543780902889760.
Arginine vasopressin, also known as antidiuretic hormone, is a neuropeptide that functions in the maintenance of body water homeostasis. Inappropriate secretion of vasopressin has been implicated in the pathophysiology of multiple diseases, including polycystic kidney disease, syndrome of inappropriate antidiuretic hormone (SIADH) secretion, and the hyponatremia commonly associated with cirrhosis and congestive heart failure. Vasopressin receptor antagonists are novel agents that block the physiologic actions of vasopressin. Lixivaptan is a vasopressin receptor antagonist with high V2 receptor affinity and is now undergoing Phase III clinical trials. Studies so far have demonstrated that Lixivaptan is efficacious in the correction of hyponatremia in SIADH, heart failure and liver cirrhosis with ascites, and few adverse effects have been noted. Thus, Lixivaptan remains a promising therapeutic modality for the treatment of multiple diseases and prevention of the associated morbidity and mortality associated with hyponatremia.
Average Rating: 5 (Based on Reviews and 37 reference(s) in Google Scholar.)
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