Identification

Name
Ataluren
Accession Number
DB05016
Type
Small Molecule
Groups
Approved
Description

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.

Structure
Thumb
Synonyms
  • 3-[5-(2-fluorophenyl)-1,2,4-oxadiazol-3-yl]benzoic acid
  • EC-000.2051
External IDs
PTC 124 / PTC-124 / PTC124
Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing End
TranslarnaGranule125 mgOralPtc Therapeutics2014-07-31Not applicableEu
TranslarnaGranule1000 mgOralPtc Therapeutics2014-07-31Not applicableEu
TranslarnaGranule250 mgOralPtc Therapeutics2014-07-31Not applicableEu
International/Other Brands
Translarna (PTC Therapeutics)
Categories
UNII
K16AME9I3V
CAS number
775304-57-9
Weight
Average: 284.242
Monoisotopic: 284.059720369
Chemical Formula
C15H9FN2O3
InChI Key
OOUGLTULBSNHNF-UHFFFAOYSA-N
InChI
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)
IUPAC Name
3-[5-(2-fluorophenyl)-1,2,4-oxadiazol-3-yl]benzoic acid
SMILES
OC(=O)C1=CC=CC(=C1)C1=NOC(=N1)C1=CC=CC=C1F

Pharmacology

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.

Structured Indications
Pharmacodynamics
Not Available
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.

Absorption

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 [6].

Volume of distribution
Not Available
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 [6].

Metabolism

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 [6].

Route of elimination

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 [6].

Half life

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

Clearance
Not Available
Toxicity
Not Available
Affected organisms
  • Humans and other mammals
Pathways
Not Available
Pharmacogenomic Effects/ADRs
Not Available

Interactions

Drug Interactions
Not Available
Food Interactions
Not Available

References

General References
  1. Welch EM, Barton ER, Zhuo J, Tomizawa Y, Friesen WJ, Trifillis P, Paushkin S, Patel M, Trotta CR, Hwang S, Wilde RG, Karp G, Takasugi J, Chen G, Jones S, Ren H, Moon YC, Corson D, Turpoff AA, Campbell JA, Conn MM, Khan A, Almstead NG, Hedrick J, Mollin A, Risher N, Weetall M, Yeh S, Branstrom AA, Colacino JM, Babiak J, Ju WD, Hirawat S, Northcutt VJ, Miller LL, Spatrick P, He F, Kawana M, Feng H, Jacobson A, Peltz SW, Sweeney HL: PTC124 targets genetic disorders caused by nonsense mutations. Nature. 2007 May 3;447(7140):87-91. Epub 2007 Apr 22. [PubMed:17450125]
  2. Hirawat S, Welch EM, Elfring GL, Northcutt VJ, Paushkin S, Hwang S, Leonard EM, Almstead NG, Ju W, Peltz SW, Miller LL: Safety, tolerability, and pharmacokinetics of PTC124, a nonaminoglycoside nonsense mutation suppressor, following single- and multiple-dose administration to healthy male and female adult volunteers. J Clin Pharmacol. 2007 Apr;47(4):430-44. [PubMed:17389552]
  3. Hamed SA: Drug evaluation: PTC-124--a potential treatment of cystic fibrosis and Duchenne muscular dystrophy. IDrugs. 2006 Nov;9(11):783-9. [PubMed:17096300]
  4. Roy B, Friesen WJ, Tomizawa Y, Leszyk JD, Zhuo J, Johnson B, Dakka J, Trotta CR, Xue X, Mutyam V, Keeling KM, Mobley JA, Rowe SM, Bedwell DM, Welch EM, Jacobson A: Ataluren stimulates ribosomal selection of near-cognate tRNAs to promote nonsense suppression. Proc Natl Acad Sci U S A. 2016 Nov 1;113(44):12508-12513. Epub 2016 Oct 4. [PubMed:27702906]
  5. Siddiqui N, Sonenberg N: Proposing a mechanism of action for ataluren. Proc Natl Acad Sci U S A. 2016 Nov 1;113(44):12353-12355. Epub 2016 Oct 19. [PubMed:27791186]
  6. EMA Product Label [Link]
External Links
KEGG Drug
D09323
PubChem Compound
11219835
PubChem Substance
175426931
ChemSpider
9394889
ChEBI
94805
ChEMBL
CHEMBL256997
PharmGKB
PA166151864
Wikipedia
Ataluren
ATC Codes
M09AX03 — Ataluren

Clinical Trials

Clinical Trials
PhaseStatusPurposeConditionsCount
1CompletedTreatmentHealthy Volunteers1
2Active Not RecruitingTreatmentAniridia1
2Active Not RecruitingTreatmentDuchenne's Muscular Dystrophy (DMD)1
2CompletedTreatmentBecker's Muscular Dystrophy (BMD) / Duchenne's Muscular Dystrophy (DMD)1
2CompletedTreatmentCystic Fibrosis (CF)4
2CompletedTreatmentDuchenne's Muscular Dystrophy (DMD)1
2RecruitingTreatmentEpilepsies1
2SuspendedTreatmentAmino Acid Metabolism, Inborn Errors1
2SuspendedTreatmentHemophilia A / Hereditary factor IX deficiency1
2TerminatedTreatmentBecker's Muscular Dystrophy (BMD) / Duchenne's Muscular Dystrophy (DMD)1
2TerminatedTreatmentDuchenne's Muscular Dystrophy (DMD)1
2, 3TerminatedTreatmentBecker's Muscular Dystrophy (BMD) / Duchenne's Muscular Dystrophy (DMD)1
3Active Not RecruitingTreatmentBecker's Muscular Dystrophy (BMD) / Duchenne's Muscular Dystrophy (DMD) / Dystrophinopathies1
3Active Not RecruitingTreatmentGenetic Diseases, Inborn / Genetic Diseases, X-Linked / Muscular Diseases / Muscular Disorders, Atrophic / Muscular Dystrophy / Muscular Dystrophy, Duchenne / Musculoskeletal Disorders / Nervous System Diseases / Neuromuscular Diseases1
3CompletedTreatmentCystic Fibrosis (CF)2
3CompletedTreatmentGenetic Diseases, Inborn / Genetic Diseases, X-Linked / Muscular Diseases / Muscular Disorders, Atrophic / Muscular Dystrophy / Muscular Dystrophy, Duchenne / Musculoskeletal Disorders / Nervous System Diseases / Neuromuscular Diseases1
3Enrolling by InvitationTreatmentBecker's Muscular Dystrophy (BMD) / Duchenne's Muscular Dystrophy (DMD)1
3RecruitingTreatmentGenetic Diseases, Inborn / Genetic Diseases, X-Linked / Muscular Diseases / Muscular Disorders, Atrophic / Muscular Dystrophy / Muscular Dystrophy, Duchenne / Musculoskeletal Disorders / Nervous System Diseases / Neuromuscular Diseases1
3TerminatedTreatmentCystic Fibrosis (CF)2
3Unknown StatusTreatmentCystic Fibrosis (CF)1
4Active Not RecruitingTreatmentCystic Fibrosis (CF)1
Not AvailableRecruitingNot AvailableMuscular Dystrophy, Duchenne1

Pharmacoeconomics

Manufacturers
Not Available
Packagers
Not Available
Dosage forms
FormRouteStrength
GranuleOral1000 mg
GranuleOral125 mg
GranuleOral250 mg
Prices
Not Available
Patents
Not Available

Properties

State
Solid
Experimental Properties
Not Available
Predicted Properties
PropertyValueSource
Water Solubility0.117 mg/mLALOGPS
logP2.96ALOGPS
logP3.92ChemAxon
logS-3.4ALOGPS
pKa (Strongest Acidic)3.9ChemAxon
pKa (Strongest Basic)-1.6ChemAxon
Physiological Charge-1ChemAxon
Hydrogen Acceptor Count4ChemAxon
Hydrogen Donor Count1ChemAxon
Polar Surface Area76.22 Å2ChemAxon
Rotatable Bond Count3ChemAxon
Refractivity94.66 m3·mol-1ChemAxon
Polarizability27.66 Å3ChemAxon
Number of Rings3ChemAxon
Bioavailability1ChemAxon
Rule of FiveYesChemAxon
Ghose FilterYesChemAxon
Veber's RuleNoChemAxon
MDDR-like RuleNoChemAxon
Predicted ADMET features
PropertyValueProbability
Human Intestinal Absorption+1.0
Blood Brain Barrier+0.9681
Caco-2 permeable-0.5391
P-glycoprotein substrateNon-substrate0.8144
P-glycoprotein inhibitor INon-inhibitor0.8905
P-glycoprotein inhibitor IINon-inhibitor0.9784
Renal organic cation transporterNon-inhibitor0.9401
CYP450 2C9 substrateNon-substrate0.8214
CYP450 2D6 substrateNon-substrate0.8367
CYP450 3A4 substrateNon-substrate0.661
CYP450 1A2 substrateInhibitor0.7977
CYP450 2C9 inhibitorNon-inhibitor0.7856
CYP450 2D6 inhibitorNon-inhibitor0.885
CYP450 2C19 inhibitorInhibitor0.5857
CYP450 3A4 inhibitorNon-inhibitor0.8332
CYP450 inhibitory promiscuityLow CYP Inhibitory Promiscuity0.5533
Ames testNon AMES toxic0.7057
CarcinogenicityNon-carcinogens0.7693
BiodegradationNot ready biodegradable0.9828
Rat acute toxicity2.3907 LD50, mol/kg Not applicable
hERG inhibition (predictor I)Weak inhibitor0.997
hERG inhibition (predictor II)Non-inhibitor0.8984
ADMET data is predicted using admetSAR, a free tool for evaluating chemical ADMET properties. (23092397)

Spectra

Mass Spec (NIST)
Not Available
Spectra
SpectrumSpectrum TypeSplash Key
Predicted MS/MS Spectrum - 10V, Positive (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 20V, Positive (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 40V, Positive (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 10V, Negative (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 20V, Negative (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 40V, Negative (Annotated)Predicted LC-MS/MSNot Available

Taxonomy

Description
This compound belongs to the class of organic compounds known as phenyloxadiazoles. These are polycyclic aromatic compounds containing a benzene ring linked to a 1,2,4-oxadiazole ring through a CC or CN bond.
Kingdom
Organic compounds
Super Class
Organoheterocyclic compounds
Class
Azoles
Sub Class
Oxadiazoles
Direct Parent
Phenyloxadiazoles
Alternative Parents
Benzoic acids / Benzoyl derivatives / Fluorobenzenes / Aryl fluorides / Heteroaromatic compounds / Oxacyclic compounds / Monocarboxylic acids and derivatives / Carboxylic acids / Azacyclic compounds / Organopnictogen compounds
show 5 more
Substituents
Phenyl-1,2,4-oxadiazole / Benzoic acid or derivatives / Benzoic acid / Benzoyl / Fluorobenzene / Halobenzene / Aryl fluoride / Aryl halide / Monocyclic benzene moiety / Benzenoid
show 16 more
Molecular Framework
Aromatic heteromonocyclic compounds
External Descriptors
Not Available

Enzymes

1. UDP-glucuronosyltransferase 1A9
Kind
Protein
Organism
Human
Pharmacological action
No
Actions
Substrate
References
  1. EMA Product Label [Link]
Kind
Protein
Organism
Human
Pharmacological action
No
Actions
Inhibitor
General Function
Sodium-independent organic anion transmembrane transporter activity
Specific Function
Involved in the renal elimination of endogenous and exogenous organic anions. Functions as organic anion exchanger when the uptake of one molecule of organic anion is coupled with an efflux of one ...
Gene Name
SLC22A6
Uniprot ID
Q4U2R8
Uniprot Name
Solute carrier family 22 member 6
Molecular Weight
61815.78 Da
References
  1. EMA Product Label [Link]
Kind
Protein
Organism
Human
Pharmacological action
No
Actions
Inhibitor
General Function
Sodium-independent organic anion transmembrane transporter activity
Specific Function
Plays an important role in the excretion/detoxification of endogenous and exogenous organic anions, especially from the brain and kidney. Involved in the transport basolateral of steviol, fexofenad...
Gene Name
SLC22A8
Uniprot ID
Q8TCC7
Uniprot Name
Solute carrier family 22 member 8
Molecular Weight
59855.585 Da
References
  1. EMA Product Label [Link]
Kind
Protein
Organism
Human
Pharmacological action
No
Actions
Inhibitor
General Function
Sodium-independent organic anion transmembrane transporter activity
Specific Function
Mediates the Na(+)-independent uptake of organic anions such as 17-beta-glucuronosyl estradiol, taurocholate, triiodothyronine (T3), leukotriene C4, dehydroepiandrosterone sulfate (DHEAS), methotre...
Gene Name
SLCO1B3
Uniprot ID
Q9NPD5
Uniprot Name
Solute carrier organic anion transporter family member 1B3
Molecular Weight
77402.175 Da
References
  1. EMA Product Label [Link]

Drug created on October 21, 2007 16:23 / Updated on December 01, 2017 15:34