- Tienilic acid
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Tienilic acid 
Systematic (IUPAC) name [2,3-dichloro-4-(2-thienylcarbonyl)phenoxy]acetic acid Clinical data Pregnancy cat. ? Legal status Withdrawn Routes Oral Pharmacokinetic data Protein binding 95% Metabolism Hepatic Half-life 6 hours Excretion Renal and biliary Identifiers CAS number 40180-04-9 ATC code C03CC02 PubChem CID 38409 UNII HC95205SY4 
KEGG D02386 ChEMBL CHEMBL267744 Chemical data Formula C13H8Cl2O4S Mol. mass 331.17 g/mol SMILES eMolecules & PubChem Tienilic acid (INN and BAN) or ticrynafen (USAN) is a diuretic drug with uric acid-lowering (uricosuric) action, formerly marketed for the treatment of hypertension. It was withdrawn in 1982, shortly after its introduction to the market, after case reports in the United States indicated a link between the use of ticrynafen and hepatitis.[1]
Criminal charges were brought against SmithKline executives with regard to hiding data related to toxicity while gaining FDA approval. The company pleaded guilty to 14 counts of failure to report adverse reactions and 20 counts of selling a misbranded drug. See United States v. SmithKline Beckman et al {BLR 286} Biotechnology Law Report. September–October 1984, 3(9-10): 206-214.
Tienilic acid was found to act as a suicide substrate at the cytochrome P450 enzymes involved in drug metabolism. Unfortunately, the metabolic reaction carried out by these enzymes converted tienilic acid to a thiophene sulfoxide which proved highly electrophilic. This encouraged a Michael reaction leading to alkylation of a thiol group in the enzyme's active site. Loss of water from the thiophene sulfoxide restored the thiophene ring and resulted in tienilic acid being covalently linked to the enzyme, thus inhibiting the enzyme irreversibly.
The above explanation is an hypothesis. It is still not known (after 15 years) if the reactive intermediate which inactivates the CYP2C9 is the thiophene sulfoxide or the thiophene epoxide. The target on the protein is also not known (could be multiple). However tienilic acid is a good mechanism based inhibitor of CYP2C9 and seems to inactivate it stoechiometrically. Progress in proteomics may one day give the answer.
References
- ^ Manier JW, Chang WW, Kirchner JP, Beltaos E (1982). Hepatotoxicity associated with ticrynafen – a uricosuric diuretic. Am J Gastroenterol 77 (6), 401–4. PMID 7091125
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