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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
Structure of TICRYNAFEN

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)

HIDE SMILES / InChI

Description

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 It was withdrawn from the market only months after its introduction because of reports of serious incidents of drug-induced liver injury including some fatalities.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 TargetPharmacologyConditionPotency

Conditions

ConditionModalityTargetsHighest PhaseProduct
Primary
SELACRYN

Cmax

ValueDoseCo-administeredAnalytePopulation
10.1 mg/dL
1000 mg single, oral
TICRYNAFEN plasma
Homo sapiens
2.48 mg/dL
250 mg single, oral
TICRYNAFEN plasma
Homo sapiens
4.48 mg/dL
500 mg single, oral
TICRYNAFEN plasma
Homo sapiens

T1/2

ValueDoseCo-administeredAnalytePopulation
1.56 h
250 mg single, oral
TICRYNAFEN plasma
Homo sapiens
2.43 h
500 mg single, oral
TICRYNAFEN plasma
Homo sapiens

Funbound

ValueDoseCo-administeredAnalytePopulation
2%
1000 mg single, oral
TICRYNAFEN plasma
Homo sapiens
2%
250 mg single, oral
TICRYNAFEN plasma
Homo sapiens
2%
500 mg single, oral
TICRYNAFEN plasma
Homo sapiens

Doses

AEs

Overview

CYP3A4CYP2C9CYP2D6hERG


OverviewOther

Other InhibitorOther SubstrateOther Inducer

Drug as perpetrator​

Drug as victim

PubMed

Sample Use Guides

In Vivo Use Guide
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
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.