Details
| Stereochemistry | ACHIRAL |
| Molecular Formula | C27H21ClFN3O2 |
| Molecular Weight | 473.926 |
| Optical Activity | NONE |
| Defined Stereocenters | 0 / 0 |
| E/Z Centers | 0 |
| Charge | 0 |
SHOW SMILES / InChI
SMILES
CC1=C(C=C(F)C=C1)C(=O)NC2=CC(Cl)=C(C=C2)C(=O)N3CC4=CC=CN4CC5=C3C=CC=C5
InChI
InChIKey=PPHTXRNHTVLQED-UHFFFAOYSA-N
InChI=1S/C27H21ClFN3O2/c1-17-8-9-19(29)13-23(17)26(33)30-20-10-11-22(24(28)14-20)27(34)32-16-21-6-4-12-31(21)15-18-5-2-3-7-25(18)32/h2-14H,15-16H2,1H3,(H,30,33)
DescriptionCurator's Comment: description was created based on several sources, including:
http://www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/CardiovascularandRenalDrugsAdvisoryCommittee/UCM318867.pdf
http://www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/CardiovascularandRenalDrugsAdvisoryCommittee/UCM320601.pdf
Curator's Comment: description was created based on several sources, including:
http://www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/CardiovascularandRenalDrugsAdvisoryCommittee/UCM318867.pdf
http://www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/CardiovascularandRenalDrugsAdvisoryCommittee/UCM320601.pdf
Lixivaptan is an orally-active, vasopressin 2 receptor antagonist. It is indicated for the treatment of symptomatic hypervolemic and euvolemic hyponatremia, associated with heart failure (HF) and syndrome of inappropriate antidiuretic hormone (SIADH). Adverse events likely to be result of the pharmacologic action of lixivaptan are: constipation, dry mouth, dizziness, insomnia. Grapefruit juice significantly increased the extent of lixivaptan absorption as compared to lixivaptan administered under fasted conditions but not under fed conditions. Lixivaptan Cmax and AUC∞ increased by 2.4-fold and 3.2-fold, respectively, when lixivaptan was administered with ketoconazole (the same in case of Simvastatin).
Approval Year
Targets
| Primary Target | Pharmacology | Condition | Potency |
|---|---|---|---|
| 0.48 nM [Ki] | |||
| 4.4 µM [IC50] | |||
| 0.57 µM [IC50] | |||
| 0.79 µM [IC50] | |||
Target ID: P37288 Gene ID: 552.0 Gene Symbol: AVPR1A Target Organism: Homo sapiens (Human) |
55.0 nM [Ki] |
Conditions
| Condition | Modality | Targets | Highest Phase | Product |
|---|---|---|---|---|
| Primary | Unknown Approved UseUnknown |
Cmax
| Value | Dose | Co-administered | Analyte | Population |
|---|---|---|---|---|
1877 ng/mL EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/12395330 |
300 mg single, oral dose: 300 mg route of administration: Oral experiment type: SINGLE co-administered: |
LIXIVAPTAN plasma | Homo sapiens population: UNHEALTHY age: ADULT sex: FEMALE / MALE food status: FASTED |
|
719 ng/mL EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/12395330 |
100 mg single, oral dose: 100 mg route of administration: Oral experiment type: SINGLE co-administered: |
LIXIVAPTAN plasma | Homo sapiens population: UNHEALTHY age: ADULT sex: FEMALE / MALE food status: FASTED |
|
183 ng/mL EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/12395330 |
25 mg single, oral dose: 25 mg route of administration: Oral experiment type: SINGLE co-administered: |
LIXIVAPTAN plasma | Homo sapiens population: UNHEALTHY age: ADULT sex: FEMALE / MALE food status: FASTED |
|
1208 ng/mL EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/12395330 |
200 mg single, oral dose: 200 mg route of administration: Oral experiment type: SINGLE co-administered: |
LIXIVAPTAN plasma | Homo sapiens population: UNHEALTHY age: ADULT sex: FEMALE / MALE food status: FASTED |
|
210 ng/mL EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/12395330 |
50 mg single, oral dose: 50 mg route of administration: Oral experiment type: SINGLE co-administered: |
LIXIVAPTAN plasma | Homo sapiens population: UNHEALTHY age: ADULT sex: MALE food status: FASTED |
AUC
| Value | Dose | Co-administered | Analyte | Population |
|---|---|---|---|---|
14884 ng × h/mL EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/12395330 |
300 mg single, oral dose: 300 mg route of administration: Oral experiment type: SINGLE co-administered: |
LIXIVAPTAN plasma | Homo sapiens population: UNHEALTHY age: ADULT sex: FEMALE / MALE food status: FASTED |
|
4391 ng × h/mL EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/12395330 |
100 mg single, oral dose: 100 mg route of administration: Oral experiment type: SINGLE co-administered: |
LIXIVAPTAN plasma | Homo sapiens population: UNHEALTHY age: ADULT sex: FEMALE / MALE food status: FASTED |
|
499 ng × h/mL EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/12395330 |
25 mg single, oral dose: 25 mg route of administration: Oral experiment type: SINGLE co-administered: |
LIXIVAPTAN plasma | Homo sapiens population: UNHEALTHY age: ADULT sex: FEMALE / MALE food status: FASTED |
|
8775 ng × h/mL EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/12395330 |
200 mg single, oral dose: 200 mg route of administration: Oral experiment type: SINGLE co-administered: |
LIXIVAPTAN plasma | Homo sapiens population: UNHEALTHY age: ADULT sex: FEMALE / MALE food status: FASTED |
|
953 ng × h/mL EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/12395330 |
50 mg single, oral dose: 50 mg route of administration: Oral experiment type: SINGLE co-administered: |
LIXIVAPTAN plasma | Homo sapiens population: UNHEALTHY age: ADULT sex: MALE food status: FASTED |
T1/2
| Value | Dose | Co-administered | Analyte | Population |
|---|---|---|---|---|
21.62 h EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/12395330 |
300 mg single, oral dose: 300 mg route of administration: Oral experiment type: SINGLE co-administered: |
LIXIVAPTAN plasma | Homo sapiens population: UNHEALTHY age: ADULT sex: FEMALE / MALE food status: FASTED |
|
9.05 h EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/12395330 |
100 mg single, oral dose: 100 mg route of administration: Oral experiment type: SINGLE co-administered: |
LIXIVAPTAN plasma | Homo sapiens population: UNHEALTHY age: ADULT sex: FEMALE / MALE food status: FASTED |
|
14.61 h EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/12395330 |
25 mg single, oral dose: 25 mg route of administration: Oral experiment type: SINGLE co-administered: |
LIXIVAPTAN plasma | Homo sapiens population: UNHEALTHY age: ADULT sex: FEMALE / MALE food status: FASTED |
|
22.56 h EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/12395330 |
200 mg single, oral dose: 200 mg route of administration: Oral experiment type: SINGLE co-administered: |
LIXIVAPTAN plasma | Homo sapiens population: UNHEALTHY age: ADULT sex: FEMALE / MALE food status: FASTED |
|
12.49 h EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/12395330 |
50 mg single, oral dose: 50 mg route of administration: Oral experiment type: SINGLE co-administered: |
LIXIVAPTAN plasma | Homo sapiens population: UNHEALTHY age: ADULT sex: MALE food status: FASTED |
Doses
| Dose | Population | Adverse events |
|---|---|---|
300 mg single, oral Highest studied dose Dose: 300 mg Route: oral Route: single Dose: 300 mg Sources: Page: p.1202 |
unhealthy, ADULT n = 5 Health Status: unhealthy Condition: Cirrhosis Age Group: ADULT Sex: M+F Food Status: FASTED Population Size: 5 Sources: Page: p.1202 |
|
250 mg 2 times / day multiple, oral Studied dose Dose: 250 mg, 2 times / day Route: oral Route: multiple Dose: 250 mg, 2 times / day Sources: Page: p.187, 188 |
unhealthy, ADULT n = 10 Health Status: unhealthy Condition: cirrhosis of liver Age Group: ADULT Sex: M+F Food Status: UNKNOWN Population Size: 10 Sources: Page: p.187, 188 |
Disc. AE: Blood sodium increased... AEs leading to discontinuation/dose reduction: Blood sodium increased (50%) Sources: Page: p.187, 188 |
AEs
| AE | Significance | Dose | Population |
|---|---|---|---|
| Blood sodium increased | 50% Disc. AE |
250 mg 2 times / day multiple, oral Studied dose Dose: 250 mg, 2 times / day Route: oral Route: multiple Dose: 250 mg, 2 times / day Sources: Page: p.187, 188 |
unhealthy, ADULT n = 10 Health Status: unhealthy Condition: cirrhosis of liver Age Group: ADULT Sex: M+F Food Status: UNKNOWN Population Size: 10 Sources: Page: p.187, 188 |
PubMed
| Title | Date | PubMed |
|---|---|---|
| 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. | 1998 Jul 2 |
|
| Binding properties of a selective tritiated vasopressin V2 receptor antagonist, [H]-SR 121463. | 2000 Oct |
Sample Use Guides
The starting dose for hospitalized patients with hyponatremia is 50 mg once daily (25 mg for outpatients) without regard to meals. The dose may be doubled every 24 hours depending on individual patient response to a maximum of 100 mg once daily (total daily dose 100 mg) in syndrome of inappropriate antidiuretic hormone patients and to a maximum of 100 mg BID (total daily dose 200 mg) in heart failure patients, as needed, to achieve the desired sodium concentration.
Route of Administration:
Oral
In Vitro Use Guide
Sources: Zingg, H.H., Bourque, W.C., Bichet, D.G. (2012) 'Vasopressin and Oxytocin: Molecular, Cellular, and Clinical Advances', p.440 Retrieved from https://books.google.ru/books?id=eaXfBwAAQBAJ
Scatchard analysis of binding to cloned human V2-receptors showed that the dissociation constant (Kd) of [3H]-AVP increased from 0.79 nM in the vehicle-control to 1.04 nM in the presence of 0.5 nM VPA-985, while the maximum binding (B max) remained unchanged (1.14 vs. 1.02 fmole/ug protein, respectively).
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NCI_THESAURUS |
C2180
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FDA ORPHAN DRUG |
589617
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CHEMBL49429
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KK-109
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DB06666
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8006
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100000126015
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172997
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C74429
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168079-32-1
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DTXSID00168472
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LIXIVAPTAN
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SUB32850
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m6876
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8F5X4B082E
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C409452
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ACTIVE MOIETY
