This premature “stop” signal (a class I mutation) stops the cell from manufacturing a full-length CFTR protein[1]. Ataluren (PTC124)-a novel chemical entity that selectively stimulates ribosomal readthrough of premature but not normal termination codons[2].

After 2–8 weeks of medication exposure, ataluren (PTC124) activity, which was optimized using nonsense-containing reporters, rescues striated muscle function in mdx mice and increases the production of dystrophin in primary muscle cells from humans and mdx mice expressing dystrophin nonsense alleles. In animals, ataluren (PTC124) is well tolerated at plasma exposures significantly higher than those needed for nonsense suppression[2]. Male Cln1R151X mice are injected intraperitoneally (ip) with the read-through drug Ataluren (PTC124) at two months of age in order to increase PPT1 enzyme activity and induce nonsense suppression. In a proof-of-principle study, these treatments are given four times a day for two days in a row. When Ataluren (PTC124) was used at a dose of 10 mg/kg, it was found to increase PPT1 enzyme activity (P=0.0001 by unpaired t-test) and protein level (P=0.0014 by unpaired t-test) in the liver, but not in the cortex. The probable cause of this tissue-specific effect is Ataluren (PTC124)'s incapacity to cross the blood brain barrier (BBB), which reduced the drug's bioavailability in the brain and kept it from building up to an effective concentration during the therapeutic window[3].

Absorption, Distribution and Excretion
Peak plasma levels of ataluren are attained approximately 1.5 hours after dosing in subjects who received medicinal product within 30 minutes of a meal.
After a single oral dose of radiolabeled ataluren, approximately half of the administered radioactive dose is recovered in the faeces and the remainder was recovered in the urine. In the urine, unchanged ataluren and the acyl glucuronide metabolite account for less than 1% and 49%, respectively, of the administered dose.

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Metabolism / Metabolites
Ataluren is metabolized by conjugation via uridine diphosphate glucuronosyltransferase (UGT) enzymes, predominantly UGT1A9 in liver and intestine. In vivo, the only metabolite detected in plasma after oral administration of radio-labelled ataluren was the ataluren-O-1β-acyl glucuronide; exposure to this metabolite in humans was approximately 8% of the plasma AUC of ataluren.

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Biological Half-Life
Ataluren plasma half-life ranges from 2-6 hours and is unaffected either by dose or repeated administration.

Protein Binding
Ataluren is 99.6% bound to human plasma proteins and the binding is independent of plasma concentration. Ataluren does not distribute into red blood cells.

[1]. CFTR Modulators for the Treatment of Cystic Fibrosis. P T. 2014 Jul;39(7):500-11.

[2]. PTC124 targets genetic disorders caused by nonsense mutations. Nature, 2007, 447(7140), 87-91.

[3]. The novel Cln1(R151X) mouse model of infantile neuronal ceroid lipofuscinosis (INCL) for testing nonsense suppression therapy. Hum Mol Genet. 2015 Jan 1;24(1):185-96.

3-[5-(2-fluorophenyl)-1,2,4-oxadiazol-3-yl]benzoic acid is a ring assembly and an oxadiazole.
Ataluren is a novel, orally administered drug that targets nonsense mutations. Ataluren is approved for use by the European Medicines Agency to treat Duchenne Muscular Dystrophy in patients aged 5 years and older who are able to walk. More specifically, ataluren is used in the small group of patients whose disease is caused by a specific genetic defect (called a ‘nonsense mutation’) in the dystrophin gene. This drug does not yet have approval by the US Food and Drug Administration or by Health Canada for any indications.

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Drug Indication
Ataluren is approved for use by the European Medicines Agency to treat Duchenne Muscular Dystrophy in patients aged 5 years and older who are able to walk. More specifically, ataluren is used in the small group of patients whose disease is caused by a specific genetic defect (called a ‘nonsense mutation’) in the dystrophin gene.
Translarna is indicated for the treatment of Duchenne muscular dystrophy resulting from a nonsense mutation in the dystrophin gene, in ambulatory patients aged 2 years and older. Efficacy has not been demonstrated in non-ambulatory patients. The presence of a nonsense mutation in the dystrophin gene should be determined by genetic testing.
Treatment of dystrophinopathy
Treatment of cystic fibrosis

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Mechanism of Action
Ataluren enables ribosomal readthrough of mRNA containing premature stop codons that otherwise would result in premature termination of protein chains. Use of ataluren allows cellular machinery to bypass nonsense mutations in genetic material, continue the translation process, and thereby restore the production of a full-length, functional protein. The research on the effects of Ataluren on the translation and stability of nonsense-containing mRNA in vitor show that Ataluren promoted readthrough at each of the nonsense codons, showing maximal activity with UGA, while having no effect on mRNA levels. Unlike the stable cell line assays, Ataluren did not discriminate significantly between the UAG and UAA mRNAs. Ataluren was a more potent nonsense-suppressing agent than gentamicin, and exhibited 4- to 15-fold stimulation of in vitro readthrough relative to the controls at levels similar to those in the stable cell reporter assays. These results indicate that Ataluren modulates termination efficiency at premature nonsense codons.

C15H9FN2O3

284.24

284.059

775304-57-9

11219835

White to off-white solid powder

1.4±0.1 g/cm3

503.7±60.0 °C at 760 mmHg

258.4±32.9 °C

0.0±1.4 mmHg at 25°C

1.604

3.73

1

6

3

21

382

0

OOUGLTULBSNHNF-UHFFFAOYSA-N

InChI=1S/C15H9FN2O3/c16-12-7-2-1-6-11(12)14-17-13(18-21-14)9-4-3-5-10(8-9)15(19)20/h1-8H,(H,19,20)

3-[5-(2-fluorophenyl)-1,2,4-oxadiazol-3-yl]benzoic acid

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)

Solubility in Formulation 1: 2.5 mg/mL (8.80 mM) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (add these co-solvents sequentially from left to right, and one by one), suspension solution; with sonication.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 900 μL of 20% SBE-β-CD physiological saline solution and mix evenly.
Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution.

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Solubility in Formulation 2: ≥ 2.08 mg/mL (7.32 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.
Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution.

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Solubility in Formulation 3: (saturation unknown) in 1% DMSO +30% polyethylene glycol+1% Tween 80 : 30mg/mL (add these co-solvents sequentially from left to right, and one by one),
Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution.

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 (Please use freshly prepared in vivo formulations for optimal results.)