TICRYNAFEN

US Previously Marketed

First approved in 1979

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 Search

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
Sources: https://www.ncbi.nlm.nih.gov/pubmed/7091125 | https://www.ncbi.nlm.nih.gov/pubmed/18838506 | https://www.ncbi.nlm.nih.gov/pubmed/22462724

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 It was withdrawn from the market only months after its introduction because of reports of serious incidents of drug-induced liver injury including some fatalities.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
Cytochrome P450 2C9 50 Target ID: P11712 Gene ID: 1559.0 Gene Symbol: CYP2C9 Target Organism: Homo sapiens (Human) Sources: https://www.ncbi.nlm.nih.gov/pubmed/18838506	Inhibitor 8297

Conditions

Condition	Modality	Targets	Highest Phase	Product
Hypertension 567 Sources: https://www.ncbi.nlm.nih.gov/pubmed/319271	Primary		Withdrawn	SELACRYN Approved Use Unknown

C_max

Value	Dose	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

T_1/2

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

F_unbound

Value	Dose	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: https://pubmed.ncbi.nlm.nih.gov/7351817	unhealthy, 30-69 years n = 3 Health Status: unhealthy Condition: arterial hypertension Age Group: 30-69 years Sex: M Population Size: 3 Sources: https://pubmed.ncbi.nlm.nih.gov/7351817	Disc. AE: Back pain, Prothrombin time increased... AEs leading to discontinuation/dose reduction: Back pain (severe, 1 patient) Prothrombin time increased (grade 5, 1 patient) Partial thromboplastin time prolonged (grade 5, 1 patient) Sources: https://pubmed.ncbi.nlm.nih.gov/7351817
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: https://pubmed.ncbi.nlm.nih.gov/7091125	unhealthy n = 57 Health Status: unhealthy Population Size: 57 Sources: https://pubmed.ncbi.nlm.nih.gov/7091125	Disc. AE: Hepatotoxicity... AEs leading to discontinuation/dose reduction: Hepatotoxicity Sources: https://pubmed.ncbi.nlm.nih.gov/7091125

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: https://pubmed.ncbi.nlm.nih.gov/7351817	unhealthy, 30-69 years n = 3 Health Status: unhealthy Condition: arterial hypertension Age Group: 30-69 years Sex: M Population Size: 3 Sources: https://pubmed.ncbi.nlm.nih.gov/7351817
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: https://pubmed.ncbi.nlm.nih.gov/7351817	unhealthy, 30-69 years n = 3 Health Status: unhealthy Condition: arterial hypertension Age Group: 30-69 years Sex: M Population Size: 3 Sources: https://pubmed.ncbi.nlm.nih.gov/7351817
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: https://pubmed.ncbi.nlm.nih.gov/7351817	unhealthy, 30-69 years n = 3 Health Status: unhealthy Condition: arterial hypertension Age Group: 30-69 years Sex: M Population Size: 3 Sources: https://pubmed.ncbi.nlm.nih.gov/7351817
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: https://pubmed.ncbi.nlm.nih.gov/7091125	unhealthy n = 57 Health Status: unhealthy Population Size: 57 Sources: https://pubmed.ncbi.nlm.nih.gov/7091125

Overview

CYP3A4	CYP2C9	CYP2D6	hERG
	inhibitor 1767 substrate 1037

OverviewOther

Other Inhibitor	Other Substrate	Other Inducer

Drug as perpetrator

Target	Modality	Activity	Metabolite	Clinical evidence
CYP2C9 1819	inhibitor 3277 Sources: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2610245/	yes [Ki 12.5 uM]

Drug as victim

Target	Modality	Activity	Metabolite	Clinical evidence
CYP2C9 1037	substrate 3367 Sources: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2610245/	yes

Sourcing

Vendor/Aggregator	ID	URL
001 Chemical	DY553233	https://www.001chemical.com/chem/40180-04-9
3B Scientific (Wuhan) Corp	3B2-1393	http://www.3bsc.com/index/pro_info.php?id=55109
AA Blocks	AA00C0U9	https://www.aablocks.com/goods/Goods/detail?id=AA00C0U9
AHH Chemical co.,ltd	MT-59519	http://www.ahhchemical.com/product/MT-59519.html
AK Scientific, Inc. (AKSCI)	2075AH	http://www.aksci.com/item_detail.php?cat=2075AH
Aaron Chemicals	AR00C1M1	http://www.aaronchem.com/40180-04-9
Alfa Chemistry	AP40180049	https://reagents.alfa-chemistry.com/product/tienilic-acid-cas-40180-04-9-11094.html
Alichem	169006174	http://www.alichem.com/en/products/40180-04-9.html
Allbio Pharm Co., Ltd	AF13269	http://www.allbiopharm.com/product/n/AF13269
Ambeed	A333768	https://www.ambeed.com/products/40180-04-9.html
Angel Pharmatech	AG200995	http://www.angelpharmatech.com/40180-04-9.html
Angene	AGN-PC-0WH1GT	http://www.angenechemical.com/productshow/AGN-PC-0WH1GT.html
Aurora Fine Chemicals LLC	A17.924.756	http://online.aurorafinechemicals.com/info?ID=A17.924.756
Axon MedChem	1564	https://www.axonmedchem.com/product/1564
BLD Pharm	BD154113	http://www.bldpharm.com/products/40180-04-9.html
Chem Scene	CS-0012688	http://www.chemscene.com/40180-04-9.html
Chemspace	CSSB00020617500	https://chem-space.com/CSSB00020617500
Debye Scientific	DA-20731	http://www.debyesci.com/cas_40180-04-9.html
Finetech	FT-0675229	http://www.finetechnology-ind.com/prod/detail/pub/40180-04-9.html
Hairui	HR140345	http://www.hairuichem.com/en/product/40180-04-9.html
Lab Network	LN01305619	https://labnetwork.com/frontend-app/p/#!/moleculedetails/LN01305619
Molcore	MC553233	https://www.molcore.com/product/40180-04-9
Sigma-Aldrich	PH006811_ALDRICH	https://www.sigmaaldrich.com/catalog/product/aldrich/ph006811
Sigma-Aldrich	SML0505_SIGMA	https://www.sigmaaldrich.com/catalog/product/sigma/sml0505?utm_source=pubchem&utm_campaign=pubchem_2017&utm_medium=referral
Sinfoo Biotech	S021077	http://www.sinfoobiotech.com/product/1024475
Smolecule	S564984	https://www.smolecule.com/products/s564984
THE BioTek	bt-292077	https://www.thebiotek.com/product/others/bt-292077
abcr GmbH	AB334090	http://www.abcr.com/shop/en/AB334090
iChemical	EBD63675	http://www.ichemical.com/chemicals/cas-40180-04-9

PubMed

Title	Date	PubMed
		252160256
Comparison of natriuretic, uricosuric, and antihypertensive properties of tienilic acid, bendrofluazide, and spironolactone.	1979 Jan 27	369652
Adverse reactions associated with ticrynafen use.	1980 Feb 22-29	7351817
Tienilic acid in the treatment of mild to moderate hypertension.	1980 Sep-Oct	7004678
Effects of prostaglandins inhibition on changes in active and inactive renin induced by antihypertensive drugs.	1982	6756707
Hepatotoxicity associated with ticrynafen--a uricosuric diuretic.	1982 Jun	7091125
A new anti-liver-kidney microsome antibody (anti-LKM2) in tienilic acid-induced hepatitis.	1984 Mar	6368059
Drug-induced hepatitis associated with anticytoplasmic organelle autoantibodies.	1985 Sep-Oct	4029887
Human cytochrome P450 2E1 is a major autoantigen associated with halothane hepatitis.	1996 Oct-Nov	8902272
Use of isotopes and LC-MS-ESI-TOF for mechanistic studies of tienilic acid metabolic activation.	2001	11764926
Ticlopidine as a selective mechanism-based inhibitor of human cytochrome P450 2C19.	2001 Oct 9	11580286
Immune-mediated drug-induced liver disease.	2002 Aug	12362579
Substrate selectivity of human cytochrome P450 2C9: importance of residues 476, 365, and 114 in recognition of diclofenac and sulfaphenazole and in mechanism-based inactivation by tienilic acid.	2003 Jan 1	12464247
Essential requirements for substrate binding affinity and selectivity toward human CYP2 family enzymes.	2003 Jan 1	12464242
Cytochrome P450 and liver diseases.	2004 Jun	15180496
Screening procedure for detection of diuretics and uricosurics and/or their metabolites in human urine using gas chromatography-mass spectrometry after extractive methylation.	2005 Aug	16044110
Automated screening with confirmation of mechanism-based inactivation of CYP3A4, CYP2C9, CYP2C19, CYP2D6, and CYP1A2 in pooled human liver microsomes.	2005 Aug	15860655
Effects of novel ethacrynic acid derivatives on human trabecular meshwork cell shape, actin cytoskeletal organization, and transcellular fluid flow.	2005 Dec	16327147
Kinetics of tienilic acid bioactivation and functional generation of drug-protein adducts in intact rat hepatocytes.	2005 Dec 5	16257391
Automated assessment of time-dependent inhibition of human cytochrome P450 enzymes using liquid chromatography-tandem mass spectrometry analysis.	2005 Nov	16049126
Evaluation of time-dependent cytochrome P450 inhibition using cultured human hepatocytes.	2006 Aug	16679385
Ethanol oxidation into acetaldehyde by 16 recombinant human cytochrome P450 isoforms: role of CYP2C isoforms in human liver microsomes.	2006 Dec 15	17084997
Tienilic acid enhances hyperbilirubinemia in Eisai hyperbilirubinuria rats through hepatic multidrug resistance-associated protein 3 and heme oxygenase-1 induction.	2006 Jun	16543292
Toxicological significance of mechanism-based inactivation of cytochrome p450 enzymes by drugs.	2007 Jun	17612953
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	17309281
Changes in gene expression induced by tienilic Acid and sulfamethoxazole: testing the danger hypothesis.	2007 Oct	18958736
A novel approach to cyclin-dependent kinase 5/p25 inhibitors: A potential treatment for Alzheimer's disease.	2007 Oct 1	17643991
A generic method to detect electrophilic intermediates using isotopic pattern triggered data-dependent high-resolution accurate mass spectrometry.	2008 Apr	18383206
Involvement of cytochrome P450-mediated metabolism in tienilic acid hepatotoxicity in rats.	2008 Dec 15	18992796
Markers of electrophilic stress caused by chemically reactive metabolites in human hepatocytes.	2008 May	18227147
The crucial protective role of glutathione against tienilic acid hepatotoxicity in rats.	2008 Oct 15	18708081
Can in vitro metabolism-dependent covalent binding data in liver microsomes distinguish hepatotoxic from nonhepatotoxic drugs? An analysis of 18 drugs with consideration of intrinsic clearance and daily dose.	2008 Sep	18690722
Substrates, inducers, inhibitors and structure-activity relationships of human Cytochrome P450 2C9 and implications in drug development.	2009	19515014
New insights into the structural features and functional relevance of human cytochrome P450 2C9. Part I.	2009 Dec	20167001
Evaluation of the potential for drug-induced liver injury based on in vitro covalent binding to human liver proteins.	2009 Dec	19720731
Prediction of pharmacological and xenobiotic responses to drugs based on time course gene expression profiles.	2009 Dec 2	19956587
Mechanism-based inactivation of cytochrome P450 2C9 by tienilic acid and (+/-)-suprofen: a comparison of kinetics and probe substrate selection.	2009 Jan	18838506
Aqua-(2,2'-bipyridine-κN,N')bis-(thio-phene-2-carboxyl-ato-κO)copper(II).	2009 Jul 11	21583368
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	19480547
Characterization of glutathione conjugates of duloxetine by mass spectrometry and evaluation of in silico approaches to rationalize the site of conjugation for thiophene containing drugs.	2010 Aug 16	20669986
Chem2Bio2RDF: a semantic framework for linking and data mining chemogenomic and systems chemical biology data.	2010 May 17	20478034
Novel metabolic bioactivation mechanism for a series of anti-inflammatory agents (2,5-diaminothiophene derivatives) mediated by cytochrome p450 enzymes.	2010 Sep	20530221
CYP2C9-mediated metabolic activation of losartan detected by a highly sensitive cell-based screening assay.	2011 May	21321060
Differential oxidation of two thiophene-containing regioisomers to reactive metabolites by cytochrome P450 2C9.	2012 Apr 16	22329513

Patents

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.

Name

Type

Language

TICRYNAFEN

Official Name

English

TIENILIC ACID

Official Name

English

SK&F 62698

Code

English

tienilic acid [INN]

Common Name

English

SK&F-62698

Code

English

Tienilic acid [WHO-DD]

Common Name

English

TIENILIC ACID [MART.]

Common Name

English

TICRYNAFEN [MI]

Common Name

English

TICRYNAFEN [USAN]

Common Name

English

SELACRYN

Brand Name

English

Classification Tree Code System Code

WHO-ATC

C03CC02