775304-57-9 Usage
Description
Ataluren (PTC124) is a nonaminoglycoside drug that selectively induces ribosomal read-through of premature but not normal termination codons, allowing the production of full-length, functional proteins. It has been developed by PTC Therapeutics and is marketed under the trade name Translarna. Ataluren has the potential to provide treatment for genetic disorders caused by nonsense mutations, such as Duchenne's muscular dystrophy (DMD) and cystic fibrosis (CF) caused by CFTR nonsense mutations.
Uses
Used in Genetic Disorders Treatment:
Ataluren (PTC124) is used as a therapeutic agent for the treatment of genetic disorders caused by nonsense mutations, such as Duchenne's muscular dystrophy (DMD) and cystic fibrosis (CF). It works by rendering ribosomes less sensitive to premature stop or 'read-through' codons, thus allowing the production of full-length, functional proteins.
Used in Pharmaceutical Industry:
In the pharmaceutical industry, Ataluren (PTC124) is used as a drug candidate for the development of treatments targeting genetic disorders with nonsense mutations. It has been approved by the European Union in May 2014 for the treatment of Duchenne’s muscular dystrophy (DMD) and is in clinical testing for other genetic disorders.
Used in Research and Development:
Ataluren (PTC124) is used as a research tool in the study of nonsense mutations and their role in genetic disorders. It helps researchers understand the mechanism of action and potential therapeutic applications in diseases such as DMD and cystic fibrosis. The target activity of PTC-124 was initially evaluated by firefly luciferase reporter cell-based nonsense codon assay (IC50 = 7 nM), providing valuable insights into its potential effectiveness.
Features
Demonstrates oral bioavailability, and an appropriate safety toxicology profile.
In vitro
Compared with Gentamicin which is only active at much higher concentrations, PTC124 is a more potent nonsense-suppressing agent and exhibits 4-to 15-fold stimulation of read-through relative to controls. PTC124 (0.01-3 μM) promotes dose-dependent read-through of all three nonsense codons in HEK293 cells harboring LUC-190 nonsense alleles with the highest read-through at UGA, followed by UAG and then UAA, but it does not suppress multiple proximal nonsense codons. Like Gentamicin, PTC124 is most active when a pyrimidine (in particular cytosine, C) follows the nonsense codon. Consistent with the stable cell line reporter assay, PTC124 (17 μM) promotes significant production of dystrophin in primary muscle cells from Duchenne muscular dystrophy (DMD) patients or MDXMDX mice expressing dystrophin nonsense alleles. PTC124 selectively promotes ribosomal read-through of premature termination but not normal termination codons, even at concentrations substantially greater than the values achieving maximal activity.
In vivo
Due to functional recovery of dystrophin production, oral, intraperitoneal or combined dosing of PTC124 for 2-8 weeks partially rescues functional strength deficit in dystrophic muscles of MDX mice, and results in partial protection against contraction-induced injury in the extensor digitorum longus (EDL) muscles, as well as significant reductions in serum creatine kinase values. In Cftr-/-mice expressing a human CFTR-G542X transgene, subcutaneous or oral administration of PTC124 (~60 mg/kg) suppresses the G542X nonsense mutation in a dose-dependent manner, leading to a significant restoration of human (h)CFTR protein expression and function without any effect on nonsense-mediated mRNA decay (NMD) or other aspects of mRNA stability. PTC124 treatment (60 mg/kg) restores 29% of the normal intestinal transepithelial cAMP-stimulated shortcircuit currents observed in Cftr+/+ mice, displaying a significant advantage compared with Gentamicin.
Synthesis
The sequence to construct ataluren, which was described by the
authors at PTC Therapeutics, commenced with commercially available
methyl 3-cyanobenzoate (38). This ester was exposed to
hydroxylamine in aqueous tert-butanol and warmed gently until
the reaction was deemed complete. Then this mixture was treated
with 2-fluorobenzoyl chloride dropwise and subsequently triethylamine
dropwise. To minimize exotherm and undesired side products,
careful control of the addition of reagents was achieved
through slow dropwise addition of these liquid reagents. Upon
complete consumption of starting materials and formation of amidooxime
39, the aqueous reaction mixture was then heated to
85 ℃ to facilitate 1,2,4-oxadiazole formation, resulting in the tricyclic
ester 40 in excellent yield across the three steps. Finally,
saponification of ester 40 through the use of sodium hydroxide followed
by acidic quench gave ataluren (V) in 96% over the two-step
sequence.
Check Digit Verification of cas no
The CAS Registry Mumber 775304-57-9 includes 9 digits separated into 3 groups by hyphens. The first part of the number,starting from the left, has 6 digits, 7,7,5,3,0 and 4 respectively; the second part has 2 digits, 5 and 7 respectively.
Calculate Digit Verification of CAS Registry Number 775304-57:
(8*7)+(7*7)+(6*5)+(5*3)+(4*0)+(3*4)+(2*5)+(1*7)=179
179 % 10 = 9
So 775304-57-9 is a valid CAS Registry Number.
InChI:InChI=1/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)
775304-57-9Relevant articles and documents
Preparation method of Ataluren
-
, (2021/07/01)
The invention discloses a preparation method of Ataluren. The preparation method comprises an addition step in which under an alkaline condition, 3-cyanobenzoate reacts with hydroxylamine hydrochloride by using a first mixed solvent to obtain an intermediate as shown in a formula III, a condensation step in which in a first organic solvent, a condensation reaction is conducted on the intermediate shown in the formula III and o-fluorobenzoic acid to obtain an intermediate shown in a formula IV, a cyclization step in which in a second organic solvent, catalyzing is conducted by using Lewis acid, and intramolecular dehydration is conducted on the intermediate in the formula IV to obtain an intermediate in a formula V, and an ester hydrolysis step in which under an alkaline condition, ester hydrolysis is conducted on the intermediate in the formula V by using a second mixed solvent to obtain the product. Cheap raw materials are subjected to addition, condensation, cyclization and ester hydrolysis, the reaction conditions are mild, the process is simple, the cost is low, and industrial production is facilitated. Meanwhile, the solvent in the reaction process can be basically recycled, the synthesis cost is low, and the reaction environment is good; in addition, the purification operation is simple, and the total yield and the product purity of the target compound Ataluren are high.
PROCESS FOR PREPARING ATALUREN AND ITS INTERMEDIATES
-
, (2018/01/18)
The present invention provides processes for the preparation of ataluren. Intermediates for preparing ataluren are also provided.
Palladium-Catalyzed, Silver-Assisted Direct C-5–H Arylation of 3-Substituted 1,2,4-Oxadiazoles under Microwave Irradiation
Li, Shan,Wan, Penghui,Ai, Jing,Sheng, Rong,Hu, Yongzhou,Hu, Youhong
, p. 772 - 778 (2017/03/11)
A direct C-5–H arylation of 3-substituted 1,2,4-oxadiazoles with aryl iodides in the presence of a palladium catalyst and silver acetate is reported. This method provides a rapid, reliable way to obtain versatile 3,5-diaryl-1,2,4-oxadiazole derivatives, which are common moieties of many biologically active molecules. The synthetic applications of this novel method have been demonstrated in the concise syntheses of Ataluren and a potent RET inhibitor Yhhu251. (Figure presented.).
