Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

---

Query: UNIPROT:P01185 (vasopressin)
23,126 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Lixivaptan is a non-peptide, orally-active vasopressin antagonist under development by American Home Products for the potential treatment of hyponatremia associated with diseases such as heart failure, liver cirrhosis and nephrotic syndrome. By 1997, it was in phase II trials in the US and elsewhere for hyponatremia [2424051. It selectively prevents vasopressin-dependent water resorption, increasing water excretion with low electrolyte loss [266993] and is selective towards the human V2 versus V1 receptors [295987].
...
PMID:Lixivaptan (American Home Products). 1156 11

The involvement of vasopressin (AVP) in several pathological states has been reported recently and the selective blockade of the different AVP receptors could offer new clinical perspectives. During the past few years, various selective, orally active AVP V1a (OPC-21268, SR49059 (Relcovaptan)), V2 (OPC-31260, OPC-41061 (Tolvaptan), VPA-985 (Lixivaptan), SR121463, VP-343, FR-161282) and mixed V1a/V2 (YM-087 (Conivaptan), JTV-605, CL-385004) receptor antagonists have been intensively studied in various animal models and have reached, Phase IIb clinical trials for some of them. For many years now, our laboratory has focused on the identification of nonpeptide vasopressin antagonists with suitable oral bioavailability. Using random screening on small molecule libraries, followed by rational SAR and modelization, we identified a chemical series of 1-phenylsulfonylindolines which first yielded SR49059, a V1a receptor antagonist prototype. This compound displayed high affinity for animal and human V1a receptors and antagonized various V1a AVP-induced effects in vitro and in vivo (intracellular [Ca2+] increase, platelet aggregation, vascular smooth muscle cell proliferation, hypertension and coronary vasospasm). We and others have used this compound to study the role of AVP in various animal models. Recent findings from clinical trials show a potential interest for SR49059 in the treatment of dysmenorrhea and in Raynaud's disease. Structural modifications and simplifications performed in the SR49059 chemical series yielded highly specific V2 receptor antagonists (N-arylsulfonyl-oxindoles), amongst them SR121463 which possesses powerful oral aquaretic properties in various animal species and in man. SR121463 is well-tolerated and dose-dependently increases urine output and decreases urine osmolality. It induces free water-excretion without affecting electrolyte balance in contrast to classical diuretics (e.g. furosemide and hydrochlorothiazide). Notably, in cirrhotic rats with ascites and impaired renal function, a 10-day oral treatment with SR121463 (0.5 mg/kg) totally corrected hyponatremia and restored normal urine excretion. This compound also displayed interesting new properties in a rabbit model of ocular hypertension, decreasing intraocular pressure after single or repeated instillation. Thus, V2 receptor blockade could be of interest in several water-retaining diseases such as the syndrome of inappropriate antidiuretic hormone secretion (SIADH), liver cirrhosis and congestive heart failure and deserves to be widely explored. Finally, further chemical developments in the oxindole family have led to the first specific and orally active V1b receptor antagonists (with SSR149415 as a representative), an awaited class of drugs with expected therapeutic interest mainly in ACTH-secreting tumors and various emotional diseases such as stress-related disorders, anxiety and depression. However, from the recently described tissue localization for this receptor, we could also speculate on other unexpected uses. In conclusion, the development of AVP receptor antagonists is a field of intensive pharmacological and clinical investigation. Selective and orally active compounds are now available to give new insight into the pathophysiological role of AVP and to provide promising drugs.
...
PMID:Nonpeptide vasopressin receptor antagonists: development of selective and orally active V1a, V2 and V1b receptor ligands. 1243 36

Arginine vasopressin (AVP) is a neuropeptide hormone that plays an important role in circulatory and sodium homeostasis, and regulating serum osmolality. Several clinical conditions have been associated with inappropriately elevated levels of AVP including heart failure, cirrhosis of the liver and the syndrome of inappropriate secretion of antidiuretic hormone. Three receptor subtypes that mediate the actions of AVP have been identified (V(1A), V(2) and V(1B)). Activation of V(1A) receptors located in vascular smooth muscle cells and the myocardium results in vasoconstriction and increased afterload and hypertrophy. The V(2) receptors located primarily in the collecting tubules mediate free water absorption. The V(1B) receptors are located in the anterior pituitary and mediate adrenocorticotropin hormone release. The cardiovascular and renal effects of AVP are mediated primarily by V(1A) and V(2) receptors. Antagonism of V(1A) receptors results in vasodilatation and antagonism of V(2) receptors resulting in aquaresis, an electrolyte-sparing water excretion. Several non-peptide AVP antagonists (vasopressin receptor antagonists [VRAs]) also termed 'vaptans' have been developed and are vigorously being studied primarily for treating conditions characterised by hyponatraemia and fluid overload. Conivaptan is a combined V(1A)/V(2)-receptor antagonist that induces diuresis as well as haemodynamic improvement. It has been shown in clinical trials to correct euvolaemic and hypervolaemic hyponatraemia, and has been approved by the US FDA for the treatment of euvolaemic hyponatraemia as an intravenous infusion. Tolvaptan, a selective V(2)-receptor antagonist, has undergone extensive clinical studies in the treatment of hyponatraemia and heart failure. It has been shown to effectively decrease fluid in volume overloaded patients with heart failure and to correct hyponatraemia. A large outcome study (n = 4133 patients) will define its role in the management of heart failure. Lixivaptan and satavaptan (SR-121463) are other selective V(2)-receptor antagonists being evaluated for the treatment of hyponatraemia. In addition, a potential role for the vaptans in attenuating polyuria in nephrogenic diabetes insipidus and cyst development in polycystic kidney disease is being explored. Ongoing clinical trials should further define the scope of the potential therapeutic role of VRAs.
...
PMID:Therapeutic potential of vasopressin receptor antagonists. 1742 3

Small molecule agonists and antagonists of the V(2)-vasopressin receptor have been discovered and have undergone clinical trials. In conjunction with these discovery programs, the synthesis and biological testing of various metabolites associated with these clinical targets were actively pursued. We now report the results of our synthetic efforts and the corresponding biological data generated for several of the metabolites of WAY-151932 and CL-347985 (Lixivaptan).
...
PMID:Identification and synthesis of major metabolites of Vasopressin V2-receptor agonist WAY-151932, and antagonist, Lixivaptan. 1785 87

Oxytocin (OT) and vasopressin (AVP) mediate their biological actions by acting on four known receptors: The OT (uterine) and the AVP V(1a) (vasopressor), V(1b) (pituitary), V(2) (renal) receptors and a fifth putative AVP V(1c)? (vasodilating) receptor. This presentation will summarize some highlights of the recent progress, in the design and synthesis of selective peptide agonists, antagonists, radioiodinated ligands, fluorescent ligands and bivalent ligands for these receptors. Here we present published and unpublished pharmacological data on the most widely used agonists, antagonists and labelled ligands. The pharmacological properties of promising new selective OT antagonists and V(1b) agonists are also presented. This review should serve as a useful guide for the selection of the most appropriate ligand for a given study. The current status of non-peptide OT and AVP antagonists and agonists is also summarized. The relative merits of peptide and non-peptide AVP and OT agonists and antagonists as: (1) research tools and (2) therapeutic agents will be evaluated. Many of the receptor selective peptide agonists and antagonists from this and other laboratories are far more widely used as pharmacological tools for studies on the peripheral and central effects of OT and AVP than their non-peptide counterparts. In addition to OT and to a lesser extent AVP (pitressin), a number of OT and AVP analogues; such as carbetocin (OT agonist) dDAVP (desmopressin, V(2) agonist), terlipressin (V(1a) agonist), felypressin (V(1a) agonist) and atosiban (Tractocile OT antagonist) are also in clinical use. Despite much early promise, no non-peptide V(1a) or OT antagonists are currently in clinical trials. While a number of orally active non-peptide V(2) antagonists (Vaptans); notably, Tolvaptan, Lixivaptan and Satavaptan, are currently in Phase III clinical trials; to date, only the mixed V(2)/V(1a), antagonist Conivaptan (Vaprisol), has been approved by the US FDA for clinical use (by i.v. administration), for the treatment of euvolemic and hypervolemic hyponatremia in hospitalized patients. Promising new non-peptide V(1b) and OT antagonists, as well as non-peptide V(2) and OT agonists are now in pre-clinical development.
...
PMID:Peptide and non-peptide agonists and antagonists for the vasopressin and oxytocin V1a, V1b, V2 and OT receptors: research tools and potential therapeutic agents. 1865 3

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.
...
PMID:Lixivaptan: a novel vasopressin receptor antagonist. 1937 24

Vasopressin plays a physiological role in regulation of blood pressure, fluid volume, and serum osmolality. In heart failure inadequate release of vasopressin may result in excess fluid retention and hyponatremia. Vasopressin receptor antagonists are a new class of orally active drugs targeted to inhibit one or more of three distinct vasopressin receptors, namely V1a- (-->vasoconstriction), V1b- (-->release of ACTH) und V2-receptors (-->inhibition of free water reabsorption in the kidney). In cardiac decompensation with fluid overload selective V2- (Lixivaptan, satavaptan and tolvaptan) and non-selective V1a/V2-receptor blockers (Conivaptan) have been shown to be superior to standard therapy, as they allow for a faster weight loss and a more rapid symptomatic improvement (i.e. reduction in dyspnea). Inhibiting free water reabsorption without affecting renal sodium excretion vasopressin receptor antagonists allow for a controlled normalisation of serum natrium in euvolemic and hypervolemic hyponatremia. Vasopressin antagonists are well tolerated and have--in contrast to diuretics--no negative influence on renal function and serum potassium. Heart rate and blood pressure are not affected by vasopressin receptor antagonists. However, despite its excellent acute clinical effects long-term treatment with tolvaptan did not result in a reduced mortality and morbidity in heart failure patients over a mean follow-up of 9.9 months in the EVEREST trial.
...
PMID:[Vasopressin receptor antagonists and heart failure]. 1988 90

Hyponatremia is a common electrolyte disorder in patients with heart failure (HF) associated with cognitive dysfunction and increased mortality and rehospitalization rates. Loop diuretics worsen renal function, produce neurohormonal activation, and induce electrolyte imbalances. Lixivaptan is a selective, oral vasopressin V(2) -receptor antagonist that improves hyponatremia by promoting electrolyte-free aquaresis without significant side effects. The Treatment of Hyponatremia Based on Lixivaptan in NYHA Class III/IV Cardiac Patient Evaluation (BALANCE) study is a randomized, double-blind, placebo-controlled, phase 3 trial designed to evaluate the effects of lixivaptan on serum sodium in patients hospitalized with worsening heart failure (target N= 650), signs of congestion and serum sodium concentrations <135 mEq/L. Other endpoints include assessment of dyspnea, body weight, cognitive function, and days of hospital-free survival. Patients are randomized 1:1 to lixivaptan or matching placebo for 60 days, with a 30-day safety follow-up. Doses of lixivaptan or placebo are adjusted based on serum sodium and volume status. Lixivaptan was shown to increase serum sodium and reduce body weight, without renal dysfunction or hypokalemia. BALANCE seeks to address unmet questions regarding the use of vasopressin antagonists including their effects on cognitive function and clinical outcomes in patients with hyponatremia and worsening heart failure.
...
PMID:Rationale and design of the treatment of hyponatremia based on lixivaptan in NYHA class III/IV cardiac patient evaluation (THE BALANCE) study. 2097 22

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.
...
PMID:Lixivaptan, a non-peptide vasopressin V2 receptor antagonist for the potential oral treatment of hyponatremia. 2104 26

Hyponatremia is a common electrolyte disorder associated with increased morbidity and mortality, particularly in the elderly. Lixivaptan, a new selective vasopressin V2-receptor antagonist, safely corrected serum sodium concentrations in phase II studies of patients with euvolemic hyponatremia. Here our multinational, double-blind, placebo-controlled, phase III study assessed the effect of lixivaptan on serum sodium concentrations in 106 initially hospitalized patients with euvolemic hyponatremia (serum sodium less than 130 mmol/l). Of them, 52 were randomized to receive placebo and 54 received 50 mg lixivaptan once daily and were then titrated to receive 25-100 mg once daily depending on serum sodium concentration. Fluid restriction was at the investigator's discretion. Initial titration occurred in a monitored inpatient setting; patients were then treated as outpatients for a total of 30 days. The primary end point was the change in serum sodium concentration from baseline to day 7. Lixivaptan significantly increased the serum sodium concentration from baseline to day 7 (the primary end point) by 6.7 mmol/l compared with placebo (4.5 mmol/l; P=0.034). Importantly, the serum sodium concentration was normalized safely and more rapidly in patients receiving lixivaptan than placebo (P=0.004) and was well tolerated. After drug discontinuation, serum sodium concentrations decreased to near-baseline levels within 7 days. Thus, lixivaptan safely and effectively corrects serum sodium concentrations in patients with euvolemic hyponatremia.
...
PMID:Lixivaptan safely and effectively corrects serum sodium concentrations in hospitalized patients with euvolemic hyponatremia. 2372 12


1 2 Next >>

---