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Arbaclofen placarbil.svg

Arbaclofen placarbil

(3R)-3-(4-chlorophenyl)-4-[[(1S)-2-methyl-1-(2-methylpropanoyloxy)propoxy]carbonylamino]butanoic acid

NDA filed

A GABA (B) receptor agonist potentially for the treatment of muscle spasticity.

AGI-006; STX-209; OS-440

CAS No. 69308-37-8 free

847353-30-4 placarbil

Arbaclofen placarbil (ar-bac-loe-fen pla-kar-bil, also known as XP19986) is a prodrug of Rbaclofen. Arbaclofen placarbil possesses more favorable pharmacokinetic profile than baclofen, with less fluctuations in plasma drug levels. It was being developed as a potential treatment for patients with GERD and spasticity due to multiple sclerosis; however, in May 2013 XenoPort announced the termination of development because of unsuccessful results in phase III clinical trials.[1]

Arbaclofen Placerbil is a prodrug of Arbaclofen, which is a selective gamma-amino-butyric acid type B receptor agonist and the R-enantiomer of baclofen. It was discovered, and has been patented by XenoPort as a new chemical entity with an improved pharmacokinetic profile compared to baclofen, which allows for sustained release properties. ArbaclofenPlacerbil was believed to have therapeutic potential in treating gastroesophogeal reflux disease (GERD) and plasticity; however due to discouraging clinical trial results, the drug was abandoned by XenoPort in 2011 for the treatment of GERD. On May 20th, 2013, XenoPort announced plans to terminate the development of Arbaclofen Placerbil for the treatment of multiple sclerosis.

Autism spectrum disorder (ASD) is a behaviorally defined disorder which has increased in prevalence over the last two decades. Despite decades of research, no effective treatment is currently available. Animal models, as well as other lines of evidence, point to abnormalities in the balance of cortical excitation to inhibition in individuals with ASD, with this imbalance resulting in an overall increase in cortical excitation. To reduce cortical excitatory glutamate pathways, arbaclofen, a selective agonist of the gamma aminobutyric acid receptor type B, has been developed. This article reviews the evidence for this treatment for ASD using a systematic review methodology. Overall, a systematic search of the literature revealed 148 relevant references with the majority of these being review papers or news items that mentioned the potential promise of arbaclofen. Five original studies were identified, four of which used STX209, a form of arbaclofen developed by Seaside Therapeutics, Inc., and one which used R-baclofen. In an animal model, treatment of Fragile X, a genetic disease with ASD features, demonstrated a reversal of behavioral, neurological, and neuropathological features associated with the disease. One double-blind, placebo-controlled study treated children and adults with Fragile X. Results from this study were promising, with signs of improvement in social function, especially in the most severely socially impaired. Two studies, one open-label and one double-blind, placebo-controlled, were conducted in children, adolescents, and young adults with ASD. These studies suggested some improvements in socialization, although the effects were limited and may have been driven by individuals with ASD that were higher-functioning. These studies and others that have used arbaclofen for the treatment of gastroesophageal reflux suggest that arbaclofen is safe and well-tolerated. Clearly, further clinical studies are needed in order to refine the symptoms and characteristics of children with ASD that are best treated with arbaclofen.

Arbaclofen placarbil.png

 Fig. 1.

Fig. 1.

The Structures of R-baclofen (1), arbaclofen placarbil (2), R-baclofen lactam (3), and the potential γ-hydroxy metabolite of R-baclofen (4).

Route 2

Reference:1. Chem. Pharm. Bull. 1995, 43, 1302-1306.

Route 3
Route 4

Reference:1. J. Am. Chem. Soc. 2005, 127, 119-125.

2. WO2007066828A1 / US2009137819A1.

Route 5

Reference:1. US2012029230A1

Route 1

Reference:1. Tetrahedron-Asymmetr. 1992, 3, 1213-1221.

2. Tetrahedron Lett. 1991, 32, 6949-6952.

.

References

Arbaclofen placarbil
Arbaclofen placarbil.svg
Systematic (IUPAC) name
(3R)-3-(4-chlorophenyl)-4-[[[(1S)-2-methyl-1-[(2-methylpropanoyl)oxy]propoxy]carbonyl]amino]butanoic acid
Clinical data
Pregnancy
category
  • N/A
Legal status
Legal status
  • Development terminated
Identifiers
CAS Number 847353-30-4
ATC code none
PubChem CID 11281011
ChemSpider 9456008
KEGG D08861 Yes
ChEMBL CHEMBL2107312 Yes
Chemical data
Formula C19H26ClNO6
Molar mass 399.86 g/mol

///////AGI-006,  STX-209,  OS-440, Arbaclofen, autism spectrum disorder, Fragile X, gamma-aminobutyric acid, arbaclofen, R-baclofen, STX209

CC(C)[C@@H](OC(=O)C(C)C)OC(=O)NC[C@H](CC(=O)O)C1=CC=C(C=C1)Cl

DISCLAIMER

I , Dr A.M.Crasto is writing this blog to share the knowledge/views, after reading Scientific Journals/Articles/News Articles/Wikipedia. My views/comments are based on the results /conclusions by the authors(researchers). I do mention either the link or reference of the article(s) in my blog and hope those interested can read for details. I am briefly summarising the remarks or conclusions of the authors (researchers). If one believe that their intellectual property right /copyright is infringed by any content on this blog, please contact or leave message at below email address amcrasto@gmail.com. It will be removed ASAP

1 Comment

  1. Fathi SAFFAR says:

    2016-05-10 12:35 GMT+02:00 New Drug Approvals :

    > DR ANTHONY MELVIN CRASTO Ph.D posted: ” Arbaclofen placarbil > (3R)-3-(4-chlorophenyl)-4-[[(1S)-2-methyl-1-(2-methylpropanoyloxy)propoxy]carbonylamino]butanoic > acid NDA filed A GABA (B) receptor agonist potentially for the treatment of > muscle spasticity. AGI-006; STX-209; OS-440 ” >

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DR ANTHONY MELVIN CRASTO Ph.D

DR ANTHONY MELVIN CRASTO Ph.D

DR ANTHONY MELVIN CRASTO, Born in Mumbai in 1964 and graduated from Mumbai University, Completed his Ph.D from ICT, 1991,Matunga, Mumbai, India, in Organic Chemistry, The thesis topic was Synthesis of Novel Pyrethroid Analogues, Currently he is working with GLENMARK PHARMACEUTICALS LTD, Research Centre as Principal Scientist, Process Research (bulk actives) at Mahape, Navi Mumbai, India. Total Industry exp 29 plus yrs, Prior to joining Glenmark, he has worked with major multinationals like Hoechst Marion Roussel, now Sanofi, Searle India Ltd, now RPG lifesciences, etc. He has worked with notable scientists like Dr K Nagarajan, Dr Ralph Stapel, Prof S Seshadri etc, He did custom synthesis for major multinationals in his career like BASF, Novartis, Sanofi, etc., He has worked in Discovery, Natural products, Bulk drugs, Generics, Intermediates, Fine chemicals, Neutraceuticals, GMP, Scaleups, etc, he is now helping millions, has 9 million plus hits on Google on all Organic chemistry websites. His friends call him worlddrugtracker. His New Drug Approvals, Green Chemistry International, All about drugs, Eurekamoments, Organic spectroscopy international, etc in organic chemistry are some most read blogs He has hands on experience in initiation and developing novel routes for drug molecules and implementation them on commercial scale over a 29 year tenure till date Aug 2016, Around 30 plus products in his career. He has good knowledge of IPM, GMP, Regulatory aspects, he has several International patents published worldwide . He has good proficiency in Technology transfer, Spectroscopy, Stereochemistry, Synthesis, Polymorphism etc., He suffered a paralytic stroke/ Acute Transverse mylitis in Dec 2007 and is 90 %Paralysed, He is bound to a wheelchair, this seems to have injected feul in him to help chemists all around the world, he is more active than before and is pushing boundaries, He has 9 million plus hits on Google, 2.5 lakh plus connections on all networking sites, 25 Lakh plus views on dozen plus blogs, He makes himself available to all, contact him on +91 9323115463, email amcrasto@gmail.com, Twitter, @amcrasto , He lives and will die for his family, 90% paralysis cannot kill his soul., Notably he has 13 lakh plus views on New Drug Approvals Blog in 212 countries......https://newdrugapprovals.wordpress.com/ , He appreciates the help he gets from one and all, Friends, Family, Glenmark, Readers, Wellwishers, Doctors, Drug authorities, His Contacts, Physiotherapist, etc

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