Description
Cytochrome P450 enzymes function to metabolize both endogenous and exogenous compounds. Both the 3A and 2C isoforms are present in human liver of which CYP2C9 seems most highly expressed. Tienilic acid is a specific suicide substrate for CYP2C9 and CYP2C10 whereby its oxidation inactivates the enzyme. The time required to inactivate one half of the CYP2C10 enzyme at the maximal rate (t
½max) is 3.4 minutes, with a dissociation constant (KI) value of 4.3 μM.
Chemical Properties
Pale Beige Solid
Uses
A heterocycloc derivative of phenoxyacetic Acid. Uses as a diuretic, uricosuric, anhtihypertensive
Uses
Tienilic Acid is a heterocyclic derivative of phenoxyacetic acid. Tienilic acid is used as diuretic, uricosuric, antihypertensive.
Definition
ChEBI: An aromatic ketone that is 2,3-dichlorophenoxyacetic acid in which the hydrogen at position 4 on the benzene ring is replaced by a thiophenecarbonyl group. A loop diuretic used to treat hypertension, it was withdrawn from the market in 1982 due to links wi
h hepatitis.
brand name
Tienilic Acid is INN and BAN;Anp 3624;Diflarex;Fr 3068;Selcryn;Skf-62698;Ticrynafen;Ticrynapen.
World Health Organization (WHO)
Tienilic acid, a diuretic agent with uricosuric and antihypertensive
activity, was introduced in 1976. By 1979 its use had been associated with cases of
hepatic toxicity, some of which were fatal, which led to the withdrawal of the drug
in most countries in which it was marketed. In France, however, precautions
regarding the use of tienilic acid were issued by the Pharmacovigilance
Commission and the drug remained available for another decade. In 1991, it was
eventually also withdrawn there since cases of hepatitis, some of which were
fulminant, had continued to occur.
Biochem/physiol Actions
Tienilic Acid (Ticrynafen) is a P450 inhibitor, a specific suicide substrate for CYP2C9 and CYP2C10. It was once used as a loop diuretic drug with uric acid-lowering (uricosuric) actvity, but was removed from market because of hepatotoxicity.
Synthesis
Ticrynafen was prepared as follows: to the reaction flask were added 1092g (4.0 mol) of 2,3-dichloro-4-hydroxyphenyl-2-thienyl ketone, 160g (4.0 mol) of sodium hydroxide powder, 100g of sodium iodide granules and 1400 mL of water. The mixture was heated to 90-95C and the mixture was 1400g (12.0 mol) of sodium chloroacetate in 2800 mL of water added over 3 hours, while maintaining pH at 9.0-10.0 with 10N sodium hydroxide solution. after addition, the reaction mixture was heated and the pH maintained for 3 hours. The slurry was cooled. The product was separated and washed with 1N sodium hydroxide solution. After drying, the sodium salt was obtained in 98.7% yield. The wet or dry salt was suspended in 7.5 liters of water at 70C-75C. Sulfuric acid (1 Kg concentration + 800 ml water) was added within 1 hour and the mixture was stirred for another 1 hour. The white slurry was cooled, the crude acid was separated, washed with water and dried (1288 g, 97.3%). The crude acid was recrystallized from ethylene dichloride using activated carbon to give 1205.5 g of ticrynafen (91%). In this method, the potassium salt can be substituted, e.g. bromoacetate or other lower alkyl esters instead of haloacetate.
References
[1] ANNAH MANCY. The Substrate Binding Site of Human Liver Cytochrome P450 2C9: An Approach Using Designed Tienilic Acid Derivatives and Molecular Modeling[J]. Biochemistry Biochemistry, 1995, 34 33: 10365-10375. DOI:
10.1021/bi00033a007[2] De Souza, F.I., Zumiotti, A.V., and Da Silva, C.F. Neuregulins 1-α and 1-β on the regeneration the peripheral nerves[J]. Acta Ortop Bras.
[3] M. PILAR LOPEZ-GARCIA Daniel M Patrick M Dansette. Thiophene derivatives as new mechanism-based inhibitors of cytochromes P-450: Inactivation of yeast-expressed human liver cytochrome P-450 2C9 by tienilic acid[J]. Biochemistry Biochemistry, 1994, 33 1: 166-175. DOI:
10.1021/bi00167a022
