Tolvaptan
[CAS# 150683-30-0]

Identification

• Classification: Biochemical >> Inhibitor >> G protein coupled receptor(GPCR & G Protein) >> Vasopressin receptor antagonist
• Name: Tolvaptan
• Synonyms: N-[4-[(5R)-7-Chloro-5-hydroxy-2,3,4,5-tetrahydro-1-benzazepine-1-carbonyl]-3-methylphenyl]-2-methylbenzamide
• Molecular Formula: C₂₆H₂₅ClN₂O₃
• Molecular Weight: 448.94
• CAS Registry Number: 150683-30-0
• EC Number: 691-537-5
• SMILES: CC1=CC=CC=C1C(=O)NC2=CC(=C(C=C2)C(=O)N3CCCC(C4=C3C=CC(=C4)Cl)O)C

Properties

• Solubility: 100 mL (DMSO)

Safety Data

• Hazard Symbols: GHS08 Warning
• Risk Statements: H361-H362
• Safety Statements: P203-P260-P263-P264-P270-P280-P318-P405-P501

Hazard Classification

Hazard	Class	Category Code	Hazard Statement
Reproductive toxicity	Repr.	2	H361
Reproductive toxicity	Lact.	-	H362

Discovery and Applications

Tolvaptan, a selective vasopressin V2 receptor antagonist, was discovered through research aimed at developing novel treatments for hyponatremia and related conditions. Scientists at Otsuka Pharmaceutical Co., Ltd., identified tolvaptan by screening a library of compounds for their ability to selectively block the vasopressin V2 receptor, which plays a crucial role in water reabsorption in the kidneys. Tolvaptan emerged as a promising candidate due to its high affinity and specificity for the V2 receptor, leading to the inhibition of water reabsorption in the renal collecting ducts. This discovery marked a significant advancement in the treatment of hyponatremia, a condition characterized by low serum sodium levels, offering a targeted therapeutic approach to restore electrolyte balance.

Tolvaptan is indicated for the treatment of euvolemic and hypervolemic hyponatremia, where serum sodium levels are low despite normal or increased total body water. By antagonizing the V2 receptors in the kidneys, tolvaptan promotes aquaresis, leading to increased excretion of electrolyte-free water and a rise in serum sodium concentrations. Tolvaptan is particularly beneficial in managing SIADH, a condition characterized by inappropriate secretion of antidiuretic hormone (ADH), leading to water retention and dilutional hyponatremia. By blocking the effects of ADH, tolvaptan helps restore normal fluid balance and corrects hyponatremia.

Tolvaptan can be used in patients with heart failure and fluid overload who are resistant to conventional diuretic therapy. By promoting water excretion without affecting electrolyte balance, tolvaptan helps reduce edema and congestion, relieving symptoms and improving clinical outcomes. In patients with cirrhosis and ascites, tolvaptan provides an alternative treatment option for managing fluid accumulation in the abdomen. Its mechanism of action helps increase urine output and decrease ascitic fluid volume, reducing the need for paracentesis and improving patient comfort.

Tolvaptan has shown promise in slowing the progression of autosomal dominant polycystic kidney disease (ADPKD), a genetic disorder characterized by the development of numerous fluid-filled cysts in the kidneys. By inhibiting fluid secretion and reducing cyst growth, tolvaptan may delay the decline in renal function and preserve kidney function in patients with ADPKD.

Due to the risk of rapid correction of hyponatremia and fluid loss, careful monitoring of serum sodium levels and fluid balance is essential during tolvaptan therapy. Dosage titration should be individualized based on the patient's response and tolerability, with regular assessments to prevent adverse effects such as dehydration or hypernatremia. Common adverse effects of tolvaptan include thirst, dry mouth, and polyuria, which are typically mild and transient. However, patients should be educated about potential risks, including the risk of hepatotoxicity, and instructed to report any symptoms suggestive of liver injury.

References

2021. Evidence-based clinical practice guidelines for Liver Cirrhosis 2020. Journal of Gastroenterology, 56(7).
DOI: 10.1007/s00535-021-01788-x

2017. Effects of Additive Tolvaptan vs. Increased Furosemide on Heart Failure With Diuretic Resistance and Renal Impairment - Results From the K-STAR Study. Circulation Journal: Official Journal of the Japanese Circulation Society, 82(1).
DOI: 10.1253/circj.cj-17-0179

2007. Tolvaptan, an Orally Active Vasopressin V2-Receptor Antagonist - Pharmacology and Clinical Trials. Cardiovascular Drug Reviews, 25(1).
DOI: 10.1111/j.1527-3466.2007.00001.x