Details
Stereochemistry | ACHIRAL |
Molecular Formula | C13H8Cl2O4S |
Molecular Weight | 331.171 |
Optical Activity | NONE |
Defined Stereocenters | 0 / 0 |
E/Z Centers | 0 |
Charge | 0 |
SHOW SMILES / InChI
SMILES
OC(=O)COC1=C(Cl)C(Cl)=C(C=C1)C(=O)C2=CC=CS2
InChI
InChIKey=AGHANLSBXUWXTB-UHFFFAOYSA-N
InChI=1S/C13H8Cl2O4S/c14-11-7(13(18)9-2-1-5-20-9)3-4-8(12(11)15)19-6-10(16)17/h1-5H,6H2,(H,16,17)
Molecular Formula | C13H8Cl2O4S |
Molecular Weight | 331.171 |
Charge | 0 |
Count |
|
Stereochemistry | ACHIRAL |
Additional Stereochemistry | No |
Defined Stereocenters | 0 / 0 |
E/Z Centers | 0 |
Optical Activity | NONE |
Ticrynafen, or tienilic acid, is a diuretic drug with uric acid-lowering action, formerly marketed for the treatment of hypertension. It was withdrawn from the market only months after its introduction because of reports of serious incidents of drug-induced liver injury including some fatalities. Its hepatotoxicity is considered to be primarily immunoallergic in nature. Tienilic acid is a thiophene-containing mechanism-based inactivator of P450 2C9, resulting from covalent modification of the P450 2C9 protein. The bioactivation mechanism involves oxidation of the thiophene ring system.
Approval Year
Targets
Primary Target | Pharmacology | Condition | Potency |
---|---|---|---|
Target ID: P11712 Gene ID: 1559.0 Gene Symbol: CYP2C9 Target Organism: Homo sapiens (Human) Sources: https://www.ncbi.nlm.nih.gov/pubmed/18838506 |
Conditions
Condition | Modality | Targets | Highest Phase | Product |
---|---|---|---|---|
Primary | SELACRYN Approved UseUnknown |
Cmax
Value | Dose | Co-administered | Analyte | Population |
---|---|---|---|---|
10.1 mg/dL EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/7398677 |
1000 mg single, oral dose: 1000 mg route of administration: Oral experiment type: SINGLE co-administered: |
TICRYNAFEN plasma | Homo sapiens population: HEALTHY age: ADULT sex: UNKNOWN food status: UNKNOWN |
|
2.48 mg/dL EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/7398677 |
250 mg single, oral dose: 250 mg route of administration: Oral experiment type: SINGLE co-administered: |
TICRYNAFEN plasma | Homo sapiens population: HEALTHY age: ADULT sex: UNKNOWN food status: UNKNOWN |
|
4.48 mg/dL EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/7398677 |
500 mg single, oral dose: 500 mg route of administration: Oral experiment type: SINGLE co-administered: |
TICRYNAFEN plasma | Homo sapiens population: HEALTHY age: ADULT sex: UNKNOWN food status: UNKNOWN |
T1/2
Value | Dose | Co-administered | Analyte | Population |
---|---|---|---|---|
1.56 h EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/7398677 |
250 mg single, oral dose: 250 mg route of administration: Oral experiment type: SINGLE co-administered: |
TICRYNAFEN plasma | Homo sapiens population: HEALTHY age: ADULT sex: UNKNOWN food status: UNKNOWN |
|
2.43 h EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/7398677 |
500 mg single, oral dose: 500 mg route of administration: Oral experiment type: SINGLE co-administered: |
TICRYNAFEN plasma | Homo sapiens population: HEALTHY age: ADULT sex: UNKNOWN food status: UNKNOWN |
Funbound
Value | Dose | Co-administered | Analyte | Population |
---|---|---|---|---|
2% EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/7398677 |
1000 mg single, oral dose: 1000 mg route of administration: Oral experiment type: SINGLE co-administered: |
TICRYNAFEN plasma | Homo sapiens population: HEALTHY age: ADULT sex: UNKNOWN food status: UNKNOWN |
|
2% EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/7398677 |
250 mg single, oral dose: 250 mg route of administration: Oral experiment type: SINGLE co-administered: |
TICRYNAFEN plasma | Homo sapiens population: HEALTHY age: ADULT sex: UNKNOWN food status: UNKNOWN |
|
2% EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/7398677 |
500 mg single, oral dose: 500 mg route of administration: Oral experiment type: SINGLE co-administered: |
TICRYNAFEN plasma | Homo sapiens population: HEALTHY age: ADULT sex: UNKNOWN food status: UNKNOWN |
Doses
Dose | Population | Adverse events |
---|---|---|
250 mg 1 times / day multiple, oral Recommended Dose: 250 mg, 1 times / day Route: oral Route: multiple Dose: 250 mg, 1 times / day Sources: |
unhealthy, 30-69 years n = 3 Health Status: unhealthy Condition: arterial hypertension Age Group: 30-69 years Sex: M Population Size: 3 Sources: |
Disc. AE: Back pain, Prothrombin time increased... AEs leading to discontinuation/dose reduction: Back pain (severe, 1 patient) Sources: Prothrombin time increased (grade 5, 1 patient) Partial thromboplastin time prolonged (grade 5, 1 patient) |
250 mg 1 times / day multiple, oral Recommended Dose: 250 mg, 1 times / day Route: oral Route: multiple Dose: 250 mg, 1 times / day Sources: |
unhealthy n = 57 |
Disc. AE: Hepatotoxicity... AEs leading to discontinuation/dose reduction: Hepatotoxicity Sources: |
AEs
AE | Significance | Dose | Population |
---|---|---|---|
Partial thromboplastin time prolonged | grade 5, 1 patient Disc. AE |
250 mg 1 times / day multiple, oral Recommended Dose: 250 mg, 1 times / day Route: oral Route: multiple Dose: 250 mg, 1 times / day Sources: |
unhealthy, 30-69 years n = 3 Health Status: unhealthy Condition: arterial hypertension Age Group: 30-69 years Sex: M Population Size: 3 Sources: |
Prothrombin time increased | grade 5, 1 patient Disc. AE |
250 mg 1 times / day multiple, oral Recommended Dose: 250 mg, 1 times / day Route: oral Route: multiple Dose: 250 mg, 1 times / day Sources: |
unhealthy, 30-69 years n = 3 Health Status: unhealthy Condition: arterial hypertension Age Group: 30-69 years Sex: M Population Size: 3 Sources: |
Back pain | severe, 1 patient Disc. AE |
250 mg 1 times / day multiple, oral Recommended Dose: 250 mg, 1 times / day Route: oral Route: multiple Dose: 250 mg, 1 times / day Sources: |
unhealthy, 30-69 years n = 3 Health Status: unhealthy Condition: arterial hypertension Age Group: 30-69 years Sex: M Population Size: 3 Sources: |
Hepatotoxicity | Disc. AE | 250 mg 1 times / day multiple, oral Recommended Dose: 250 mg, 1 times / day Route: oral Route: multiple Dose: 250 mg, 1 times / day Sources: |
unhealthy n = 57 |
PubMed
Title | Date | PubMed |
---|---|---|
Comparison of natriuretic, uricosuric, and antihypertensive properties of tienilic acid, bendrofluazide, and spironolactone. | 1979 Jan 27 |
|
Adverse reactions associated with ticrynafen use. | 1980 Feb 22-29 |
|
Tienilic acid in the treatment of mild to moderate hypertension. | 1980 Sep-Oct |
|
Effects of prostaglandins inhibition on changes in active and inactive renin induced by antihypertensive drugs. | 1982 |
|
Hepatotoxicity associated with ticrynafen--a uricosuric diuretic. | 1982 Jun |
|
A new anti-liver-kidney microsome antibody (anti-LKM2) in tienilic acid-induced hepatitis. | 1984 Mar |
|
Drug-induced hepatitis associated with anticytoplasmic organelle autoantibodies. | 1985 Sep-Oct |
|
Human cytochrome P450 2E1 is a major autoantigen associated with halothane hepatitis. | 1996 Oct-Nov |
|
Automated screening with confirmation of mechanism-based inactivation of CYP3A4, CYP2C9, CYP2C19, CYP2D6, and CYP1A2 in pooled human liver microsomes. | 2005 Aug |
|
Automated assessment of time-dependent inhibition of human cytochrome P450 enzymes using liquid chromatography-tandem mass spectrometry analysis. | 2005 Nov |
|
Ethanol oxidation into acetaldehyde by 16 recombinant human cytochrome P450 isoforms: role of CYP2C isoforms in human liver microsomes. | 2006 Dec 15 |
|
Prediction of in vivo potential for metabolic activation of drugs into chemically reactive intermediate: correlation of in vitro and in vivo generation of reactive intermediates and in vitro glutathione conjugate formation in rats and humans. | 2007 Mar |
|
Changes in gene expression induced by tienilic Acid and sulfamethoxazole: testing the danger hypothesis. | 2007 Oct |
|
The crucial protective role of glutathione against tienilic acid hepatotoxicity in rats. | 2008 Oct 15 |
|
New insights into the structural features and functional relevance of human cytochrome P450 2C9. Part I. | 2009 Dec |
|
Evaluation of the potential for drug-induced liver injury based on in vitro covalent binding to human liver proteins. | 2009 Dec |
|
Prediction of pharmacological and xenobiotic responses to drugs based on time course gene expression profiles. | 2009 Dec 2 |
|
Mechanism-based inactivation of cytochrome P450 2C9 by tienilic acid and (+/-)-suprofen: a comparison of kinetics and probe substrate selection. | 2009 Jan |
|
Aqua-(2,2'-bipyridine-κN,N')bis-(thio-phene-2-carboxyl-ato-κO)copper(II). | 2009 Jul 11 |
|
Cocktail-substrate assay system for mechanism-based inhibition of CYP2C9, CYP2D6, and CYP3A using human liver microsomes at an early stage of drug development. | 2009 Jun |
Patents
Sample Use Guides
In Vivo Use Guide
Sources: https://www.ncbi.nlm.nih.gov/pubmed/319271
In a double-blind study, 20 hypertensive patients were randomly assigned to a six-week regimen of either ticrynafen or hydrochlorothiazide. Blood pressure was significantly reduced with both medications, although most patients required an increase in dosage from 250 to 500 mg ticrynafen daily.
Route of Administration:
Oral
In Vitro Use Guide
Sources: https://www.ncbi.nlm.nih.gov/pubmed/18838506
Human recombinant P450 2C9 was assayed for residual activity with probe substrate [(S)-flurbiprofen, diclofenac, or (S)-warfarin] after a primary incubation with various concentrations of tienilic acid, analog 1, or (±)-suprofen (0.5% total organic v/v) in triplicate in a 96-well plate format at 37°C. Inactivation by tienilic acid and (±)-suprofen was described by comparable kinact and KI values against P450 2C9-mediated (S)-flurbiprofen and diclofenac hydroxylation. Inactivation of (S)-warfarin 7-hydroxylation by both tienilic acid and (±)-suprofen was best fit to a standard hyperbolic equation, which yielded noticeably lower KI estimates [12.5 and 6.7 μM with tienilic acid and (±)-suprofen, respectively], resulting in moderately higher inactivation efficiencies, in particular for (±)-suprofen. Tienilic acid was a markedly better inactivator of P450 2C9 compared with (±)-suprofen, independent of probe substrate, with a 4- to 8-fold higher inactivation efficiency.
Substance Class |
Chemical
Created
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Edited
Fri Dec 15 15:14:22 GMT 2023
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Record UNII |
HC95205SY4
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Record Status |
Validated (UNII)
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WHO-ATC |
C03CC02
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WHO-VATC |
QC03CC02
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NCI_THESAURUS |
C921
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NCI_THESAURUS |
C49184
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3036
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HC95205SY4
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D013989
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m10856
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Tienilic acid
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2658
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CHEMBL267744
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