A chemical chaperone-based drug candidate is effective in a mouse model of amyotrophic lateral sclerosis (ALS)

ChemMedChem
Tamar GetterArie Gruzman

Abstract

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by the selective death of motor neurons and skeletal muscle atrophy. The majority of ALS cases are acquired spontaneously, with inherited disease accounting for only 10 % of all cases. Recent studies provide compelling evidence that aggregates of misfolded proteins underlie both types of ALS. Small molecules such as artificial chaperones can prevent or even reverse the aggregation of proteins associated with various human diseases. However, their very high active concentration (micromolar range) severely limits their utility as drugs. We synthesized several ester and amide derivatives of chemical chaperones. The lead compound 14, 3-((5-((4,6-dimethylpyridin-2-yl)methoxy)-5-oxopentanoyl)oxy)-N,N-dimethylpropan-1-amine oxide shows, in the micromolar concentration range, both neuronal and astrocyte protective effects in vitro; at daily doses of 10 mg kg(-1) 14 improved the neurological functions and delayed body weight loss in ALS mice. Members of this new chemical chaperone derivative class are strong candidates for the development of new drugs for ALS patients.

References

Aug 1, 1989·Journal of Medicinal Chemistry·E PopN Bodor
Jul 24, 2001·Amyotrophic Lateral Sclerosis and Other Motor Neuron Disorders : Official Publication of the World Federation of Neurology, Research Group on Motor Neuron Diseases·Z Xu
Mar 7, 2006·Current Opinion in Chemical Biology·P John Hart
May 23, 2006·Drug Metabolism and Disposition : the Biological Fate of Chemicals·Tamara S Dowers, Jeffrey P Jones
Aug 16, 2006·Neuro-degenerative Diseases·Ashutosh Tiwari, Lawrence J Hayward
Dec 22, 2006·Journal of Medicinal Chemistry·Stephen A Hitchcock, Lewis D Pennington
Jul 20, 2007·Proceedings of the National Academy of Sciences of the United States of America·Arie GruzmanJian Liu
Dec 13, 2007·Annals of Neurology·Edor KabashiGuy A Rouleau
Jan 15, 2008·Drug Discovery Today·Andrea M VincentEva L Feldman
Feb 5, 2009·Annals of Neurology·Jeffrey D Rothstein
Feb 5, 2009·Orphanet Journal of Rare Diseases·Lokesh C Wijesekera, P Nigel Leigh
Nov 19, 2009·Journal of Agricultural and Food Chemistry·Hirohisa NagahoriHideo Kaneko
Aug 13, 2011·Nature Biotechnology·Amanda M Haidet-PhillipsBrian K Kaspar
Oct 12, 2011·The Journal of Physical Chemistry. B·Samuel S ChoD Thirumalai
Jan 24, 2013·Current Topics in Medicinal Chemistry·Yuewei ShengJoan Selverstone Valentine
Jul 10, 2013·Amyotrophic Lateral Sclerosis & Frontotemporal Degeneration·Bareket DanielArie Gruzman
Jul 16, 2013·Biochimica Et Biophysica Acta·Renata Sano, John C Reed
Oct 3, 2013·Journal of Neurology·Yohei IguchiGen Sobue
Oct 12, 2013·Biotechnology and Bioengineering·Simpson GregoireInchan Kwon
Mar 29, 2014·Nature·Steve Perrin
Jun 4, 2014·Global Advances in Health and Medicine : Improving Healthcare Outcomes Worldwide·Sheila VangWalter C Low
Jun 15, 2014·Trends in Neurosciences·Steve VucicMatthew C Kiernan

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Citations

Nov 9, 2015·Journal of Biological Inorganic Chemistry : JBIC : a Publication of the Society of Biological Inorganic Chemistry·Sagiv WeintraubArie Gruzman
Jan 19, 2016·Brain Pathology·Fabiola PuentesSandra Amor
Apr 12, 2016·Brain Research·Sonam Parakh, Julie D Atkin
Nov 24, 2021·Journal of Cellular Physiology·Nida BuawangpongSiriporn C Chattipakorn

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