Ataluren
[3-[5-(2-Fluorophenyl)-1,2,4-oxadiazol-3-yl]benzoic
acid] is an orally available, small molecule compound that targets nonsense
mutation. It is the first drug in its class and appears to allow cellular
machinery to read through premature stop codons in mRNA, and thus enables the
translation process to produce full-length, functional proteins.
Ataluren is developed and approved for the treatment of nonsense mutation Duchenne muscular dystrophy (nmDMD) by EU in July 2014 [1].
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| Ataluren: 2D and 3D Structure |
Nonsense Mutations as Target for DMD
A
single nucleotide change in the DNA sequence that introduces a premature stop
codon is known as a nonsense mutation, a subset of a major class of premature
termination codon (PTC) mutations. Nonsense mutations cause premature
termination of translation resulting in the production of truncated
polypeptides, which in turn halts the ribosomal translation process at an
earlier site than normal, producing a truncated, non-functional protein [1].
Nonsense
mutations are implicated in 5-70 % of individual cases of most inherited
diseases, including Duchenne muscular dystrophy (DMD) and cystic fibrosis. Ataluren
appears to allow cellular machinery to read through premature stop codons in
mRNA, enabling the translation process to produce full length, functional
proteins.
Ataluren
Synthesis
New J
Chem 2014,38, 3062-3070: The text reports one pot synthesis of Ataluren with
an overall yield of 40%. It also reports few interesting and potent derivatives
too.
WO2007117438A2: It appears to be the industrial process. The patent also reports various pharmaceutically relevant assay and their results wrt Ataluren.
Identifications:
 |
| 1H NMR (Estimated) for Ataluren |
Experimental: 1H NMR (d6-DMSO,
400 MHz) δ 13.15-13.68 (bs,
1H), 8.62 (s, 1H), 8.31 (d, 1H, JHH = 6.8 Hz), 8.24 (t, 1H, JHH
= 7.2 Hz), 8.17 (d, 1H, JHH = 7.4 Hz), 7.77-7.82 (m, 1H), 7.73 (t,
1H, JHH = 7.6 Hz), 7.53 (dd, 1H, JHH = 10.8 Hz, JHH
= 8.4 Hz), 7.48 (t, 1H, JHH = 6.8 Hz).
 |
| 13C-NMR (Estimated) for Ataluren |
Experimental:
13C NMR (d6-DMSO, 400 MHz) δ 172.72 (d, JCF = 4.4 Hz), 167.39,
166.52, 159.95 (d, JCF = 258.0 Hz), 135.80 (d, JCF = 8.8
Hz), 132.28, 131.97, 131.97, 131.04, 130.94, 129.86, 127.76, 125.4 (d, JCF
= 3.6 Hz), 117.2 (d, JCF = 20.4 Hz), 111.6 (d, JCF = 11.2
Hz).
Sideeffects:
The most common side effects reported during Ataluren therapy were headache,
nausea and vomiting. Most Ataluren-associated adverse events were of mild or
moderate severity and Ataluren had a similar adverse event profile to placebo.
Side effects did not appear to be dose dependent.
Ataluren
should not be co-administered with intravenous aminoglycosides because of the
risk of decreased renal function.
References:
1. Ryan, N. J. Ataluren: first global approval. Drugs 2014, 74(14), 1709-14. (FMO only)
2. Gupta, P. K.; et. al. A metal-free tandem approach to prepare structurally diverse N-heterocycles: synthesis of 1,2,4-oxadiazoles and pyrimidinones. New J Chem 2014, 38, 3062-3070 (FMO only)
3. Almstead, N. G.; et. al. Methods for the production of functional protein from dna having a nonsense mutation and the treatment of disorders associated therewith. WO2007117438A2
References:
1. Ryan, N. J. Ataluren: first global approval. Drugs 2014, 74(14), 1709-14. (FMO only)
2. Gupta, P. K.; et. al. A metal-free tandem approach to prepare structurally diverse N-heterocycles: synthesis of 1,2,4-oxadiazoles and pyrimidinones. New J Chem 2014, 38, 3062-3070 (FMO only)
3. Almstead, N. G.; et. al. Methods for the production of functional protein from dna having a nonsense mutation and the treatment of disorders associated therewith. WO2007117438A2
