Dual-Action Compounds Targeting Adenosine A2A Receptor and Adenosine Transporter for Prevention and Treatment of Neurodegenerative Diseases

Abstract

The present invention provides therapeutic agents for preventing and treating neurodegenerative diseases. These agents synergistically target both the adenosine A2A receptor (A2AR) and the equilibrative nucleoside transporter 1 (ENT1).

Description

[0001]The present application claims priority to U.S. Provisional Patent Application 61 / 260, 932, filed Nov. 13, 2010, the contents of which is hereby incorporated in its entirety by reference.TECHNICAL FIELD[0002]The present invention provides the identification, synthesis and use of compound active for treating neurodegenerative diseases, such as Huntington's disease.[0003]Abbreviations: A2AR, A2A adenosine receptor; Ac2O, acetic anhydride; CGS, 6-amino-9-(5-ethylcarbamoyl-3,4-dihydroxy-oxolan-2-yl)-2-{2-[4-(2-carboxyethyl)phenyl]ethylamino}purine; DIEA, diisopropylethylamine; DMF, N,N-dimethylformamide; DML, designed multiple ligands; ENT, equilibrative nucleotide transporter, ESI, electrospray ionization; EtOAc, ethyl acetate; HD, Huntington's disease; hENT1, human equilibrative nucleoside transporter 1; HBA, hydrogen bond acceptor; HBD, hydrogen bond donor; HBTU. 2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium; HOBt, 1-hydroxybenzotriazole; HP, hydrophobic; HPLC, high-perfo...

AI Technical Summary

Benefits of technology

[0005]It has been recognized that the A2AR and the adenosine transporter (such as the equilibrative nucleoside transporter ENT1) are both localized in the striatum,10-13 where the mutant Htt aggregate.14 Inhibition of the adenosine transporter would elevate the local concentrations of adenosine, and thereby increases the efficacy in agonizing the A2AR. Interestingly, compound 1 is also found to be an ENT1 inhibitor. On the other hand, the potent immunosuppressant effect of CGS was a consequence of A2AR signaling,8 which indicates that extremely strong binding affinity to A2AR may not be a desirable property for clinically useful therapeutic agents.

Problems solved by technology

However, to design multiple-targeting ligands is often a challenging task,21,22 partly due to the difficulty in appropriate construction of the computational models for describing the interactions of the ligands with several targets, and partly due to the increased restraints of chemical synthesis, and satisfaction of physical chemical properties of compounds.

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