Dual-action Compounds for the Treatment of Neurodegenerative Diseases

Project Description
JMF3464 and its analogues were designed and synthesized for the treatment of neurodegenerative diseases such as Huntington’s Disease (HD), Amyotrophic Lateral Sclerosis (ALS), Spinocerebellar Ataxia Type 3 (SCA3), and Alzheimer’s Disease (AD). These rationally designed multiple ligands are adenosine analogs with dual actions targeting the nucleoside-specific signaling and transporter pathways localized in the brain.  These compounds are inhibitors of the adenosine transporter ENT1 and mild agonists of the A2A Adenosine Receptor (A2AR).  Oral intake of these dual-action compounds allowed them to enter the brain and ameliorated disease progression.
JMF3464 and its analogues are novel adenosine analogs superior to other
potent A2AR agonists that are associated with serious cardiovascular side effects.  These dual-function adenosine compounds improved the impaired locomotion of a mouse model of HD without altering blood pressure.
JMF3464 has a decent bioavailability (F=65%) and a good compound exposure in the target tissue (i.e., brain). There is no hERG- or CMC- related issue. JMF3464 modulates two closely related pathways localized in the brain to the sites where mutant proteins accumulate
, and offers a promising means to improve those devastating neurodegenerative diseases.

Intellectual Property
Patent applications were filed in 16 countries including USA, China, European, and Taiwan

Key Publications
  • Kao Y-H, Lin M-S, Chen C-M, Wu Y-R, Chen H-M, Lai H-L, Chern Y, and Lin C-J. 2017. Targeting ENT1 and adenosine tone for the treatment of Huntington’s disease. Human Molecular Genetics. 26, 467-478.
  • Lai C-Y, Liu Y-J, Lai H-L, Chen H-M, Kuo H-C, Liao Y-P, Chern Y. 2018. The D2 dopamine receptor interferes with the protective effect of the A2A adenosine receptor on TDP-43 mislocalization in experimental models of motor neuron degeneration. Frontiers in Neuroscience, doi: 10.3389/fnins.2018.00187.
  • Lee C-C, Chang C-P, Lin C-J, Lai H-L, Kao Y-H, Cheng S-J, Chen H-M, Liao Y-P, Faivre E, Buée L, Blum D, Fang J-M, Chern Y. 2018. Adenosine augmentation evoked by an ENT1 inhibitor improves memory impairment and neuronal plasticity in the APP/PS1 mouse model of Alzheimer’s disease. Molecular Neurobiology, doi: 10.1007/s12035-018-1030-z.

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