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Talniflumate (BA -602-06), a prodrug of Niflumic acid, is a potent,orally bioactive and selective inhibitor of core mucin-synthesizing enzyme GCNT3 (core 2b-1,6 N-acetylglucosaminyltrans-ferase). Talniflumate is a Ca2+-activated Cl- channel (CaCC) blocker and has to be converted to the active form Niflumic acid in order to exert its effects. Talniflumate can be used as an analgesic and anti-inflammatory agent in cystic fibrosis mouse model of distal intestinal obstructive syndrome.
Physicochemical Properties
| Molecular Formula | C21H13F3N2O4 |
| Molecular Weight | 414.3341 |
| Exact Mass | 414.082 |
| CAS # | 66898-62-2 |
| PubChem CID | 48229 |
| Appearance | White to yellow solid powder |
| Density | 1.5±0.1 g/cm3 |
| Boiling Point | 534.6±50.0 °C at 760 mmHg |
| Melting Point | 165-167ºC |
| Flash Point | 277.1±30.1 °C |
| Vapour Pressure | 0.0±1.4 mmHg at 25°C |
| Index of Refraction | 1.625 |
| LogP | 5.59 |
| Hydrogen Bond Donor Count | 1 |
| Hydrogen Bond Acceptor Count | 9 |
| Rotatable Bond Count | 5 |
| Heavy Atom Count | 30 |
| Complexity | 644 |
| Defined Atom Stereocenter Count | 0 |
| SMILES | FC(C1C([H])=C([H])C([H])=C(C=1[H])N([H])C1=C(C([H])=C([H])C([H])=N1)C(=O)OC1([H])C2=C([H])C([H])=C([H])C([H])=C2C(=O)O1)(F)F |
| InChi Key | ANMLJLFWUCQGKZ-UHFFFAOYSA-N |
| InChi Code | InChI=1S/C21H13F3N2O4/c22-21(23,24)12-5-3-6-13(11-12)26-17-16(9-4-10-25-17)19(28)30-20-15-8-2-1-7-14(15)18(27)29-20/h1-11,20H,(H,25,26) |
| Chemical Name | 2-[[3-(Trifluoromethyl)phenyl]amino]-3-pyridinecarboxylic acid 1,3-dihydro-3-oxo-1-isobenzofuranyl ester |
| Synonyms | BA7602-06BA 7602-06BA-7602-06 |
| HS Tariff Code | 2934.99.9001 |
| Storage |
Powder-20°C 3 years 4°C 2 years In solvent -80°C 6 months -20°C 1 month |
| Shipping Condition | Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs) |
Biological Activity
| ln Vivo | Talniflumate (oral chow; 0.4 mg/g; 21 days) dramatically enhanced survival in CF mice from 26% to 77%. It does not alter crypt goblet cell populations or modify intestinal expression of mCLCA3 but tends to diminish crypt mucoid impaction [1]. |
| Animal Protocol |
Animal/Disease Models: CF mice with distal intestinal obstruction syndrome (DIOS)[1] Doses: 0.4 mg/g Route of Administration: oral; 21-day Experimental Results: Distal intestinal obstruction syndrome cystic fibrosis mouse model The survival rate is improved. |
| ADME/Pharmacokinetics |
Absorption, Distribution and Excretion In 12 subjects after a single oral administration, total plasma clearance of the main metabolite, niflumic acid, averaged 45 ml/min giving a distribution volume of 0.12 l/kg on average. This drug undergoes extensive first pass effect. Metabolism / Metabolites Extensive liver metabolism. Biological Half-Life Approximately 2h in 12 subjects |
| Toxicity/Toxicokinetics |
Protein Binding Niflumic acid, the active form of Talniflumate, is weak acid that is strongly bound to plasma proteins. Bioavailability was 100% in a study of 12 volunteers. It is a weak acid, strongly bound to plasma proteins. |
| References |
[1]. Pharmacokinetics of talniflumate, a prodrug of niflumic acid, following oral administration to man. Archives of Pharmacal Research volume 19, Article number: 297 (1996). [2]. Agonist and Antagonist Activities on Human NPFF(2) Receptors of the NPY Ligands GR231118 and BIBP3226. Br J Pharmacol.2001 May;133(1):1-4. |
| Additional Infomation |
2-[3-(trifluoromethyl)anilino]-3-pyridinecarboxylic acid (3-oxo-1H-isobenzofuran-1-yl) ester is a member of benzofurans. Talniflumate, is an anti-inflammatory molecule studied and used as a mucin regulator in the treatment of cystic fibrosis, chronic obstructive pulmonary disease (COPD) and asthma. In addition, it is used in inflammatory conditions such as rheumatoid arthritis. Phase I trials with talniflumate for the treatment of cystic fibrosis and COPD were completed in August 2001, and phase II trials were performed in Ireland for the treatment of cystic fibrosis but this research has now been discontinued. Talniflumate has been approved for approximately 20 years in Argentina other countries (excluding the United States, Europe, and Japan). Drug Indication Talnifumate is a phthalidyl ester of nifumic acid, which has potent analgesic and anti-inflammatory effects and is widely used to treat inflammatory disorders, such as rheumatoid arthritis and osteoarthritis, and has also been studied for the management of cystic fibrosis. Mechanism of Action Talniflumate is a strong and selective inhibitor of core mucin-synthesizing enzyme GCNT3 (core 2 b-1,6 N-acetylglucosaminyltransferase). Talniflumate decreases gene expression of GCNT3 and production of mucins in vivo and in vitro. Talniflumate improves response of pancreatic tumors to gefitinib (chemotherapy drug). Talniflumate is a strong calcium-activated chloride channel (CaCC) blocker. Pharmacodynamics Talniflumate is metabolized to its prodrug, niflumic acid, which has several pharmacodynamic effects. Firstly, it blocks synthesis of mucin. Secondly, talniflumate blocks prostaglandin synthesis by cyclooxygenases, which aids in pain and inflammation management. |
Solubility Data
| Solubility (In Vitro) | DMSO : ~62.5 mg/mL (~150.85 mM) |
| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 2.08 mg/mL (5.02 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution. For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 20.8 mg/mL clear DMSO stock solution to 900 μL of corn oil and mix evenly. (Please use freshly prepared in vivo formulations for optimal results.) |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 2.4135 mL | 12.0677 mL | 24.1354 mL | |
| 5 mM | 0.4827 mL | 2.4135 mL | 4.8271 mL | |
| 10 mM | 0.2414 mL | 1.2068 mL | 2.4135 mL |