Tolvaptan

Tolvaptan

Systematic (IUPAC) name
N-(4-{[(5R)-7-chloro-5-hydroxy-2,3,4,5-tetrahydro-1H-1-benzazepin-1-yl]carbonyl}-3-methylphenyl)-2-methylbenzamide
Clinical data
Trade names	Samsca, Jinarc
AHFS/Drugs.com	monograph
MedlinePlus	a609033
Licence data	US FDA:link
Pregnancy category	US: C (Risk not ruled out)
Legal status	UK: POM (Prescription only) US: ℞-only
Routes of administration	Oral
Pharmacokinetic data
Bioavailability	Unknown (40% absorbed)
Protein binding	99%
Metabolism	Hepatic (CYP3A4-mediated)
Biological half-life	12 hours (terminal)
Identifiers
CAS Number	150683-30-0 N
ATC code	C03XA01 (WHO)
PubChem	CID: 216237
IUPHAR/BPS	2226
ChemSpider	187438 Y
UNII	21G72T1950 Y
ChEMBL	CHEMBL344159 Y
Synonyms	OPC-41061
Chemical data
Formula	C26H25ClN2O3
Molecular mass	448.941 g/mol
SMILES O=C(c1ccccc1C)Nc2ccc(c(c2)C)C(=O)N4c3ccc(Cl)cc3C(O)CCC4
InChI InChI=1S/C26H25ClN2O3/c1-16-6-3-4-7-20(16)25(31)28-19-10-11-21(17(2)14-19)26(32)29-13-5-8-24(30)22-15-18(27)9-12-23(22)29/h3-4,6-7,9-12,14-15,24,30H,5,8,13H2,1-2H3,(H,28,31) Y Key:GYHCTFXIZSNGJT-UHFFFAOYSA-N Y
NY (what is this?)  (verify)

Tolvaptan (INN, trade names Samsca and Jinarc) is a selective, competitive vasopressin receptor 2 antagonist used to treat hyponatremia (low blood sodium levels) associated with congestive heart failure, cirrhosis, and the syndrome of inappropriate antidiuretic hormone (SIADH). Tolvaptan was approved by the U.S. Food and Drug Administration (FDA) on May 19, 2009, and is sold by Otsuka Pharmaceutical Co. under the trade name Samsca and in India is manufactured & sold by MSN laboratories Ltd. under the trade name Tolsama & Tolvat and by Lupin under the brand name Resodim.

Tolvaptan was also in fast-track clinical trials for polycystic kidney disease. In a 2004 trial, tolvaptan, when administered with traditional diuretics, was noted to increase excretion of excess fluids and improve blood sodium levels in patients with heart failure without producing side effects such as hypotension (low blood pressure) or hypokalemia (decreased blood levels of potassium) and without having an adverse effect on kidney function. In a recently published trial (TEMPO 3:4 ClinicalTrials.gov number, NCT00428948) the study met its primary and secondary end points. Tolvaptan, when given at an average dose of 95 mg per day over a 3-year period, slowed the usual increase in kidney volume by 50% compared to placebo (2.80% per year versus 5.51% per year, respectively, p<0.001) and reduced the decline in kidney function when compared with that of placebo-treated patients by approximately 30% (reciprocal serum creatinine, -2.61 versus -3.81 (mg/mL)-1 per year, p <0.001)

Synthesis

Tolvaptan synthesis:

Side effects

FDA has determined that the drug Samsca (tolvaptan) should not be used for longer than 30 days and should not be used in patients with underlying liver disease because it can cause liver injury, potentially leading to liver failure