Tuesday, May 24, 2016

Ataluren | Treatment for Duchenne Muscular Dystrophy | Orphan Drug | Treatment of Nonsense Mutation

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].

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.

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.

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