50823-32-0Relevant academic research and scientific papers
Nucleoside-5′-monophosphates as prodrugs of adenosine A2A receptor agonists activated by ecto-5′-nucleotidase
El-Tayeb, Ali,Iqbal, Jamshed,Behrenswerth, Andrea,Romio, Michael,Schneider, Marion,Zimmermann, Herbert,Schrader, Jürgen,Müller, Christa E.
, p. 7669 - 7677 (2009)
Prodrugs of adenosine A2A receptor agonists were developed that are activated by ecto-5′-nucleotidase (ecto-5′-NT,CD73). Because ecto-5′-NT is upregulated in inflamed tissue, the A2A agonists are expected to be released from their prodrug form at the sites of inflammation. 2-(Ar)alkyl-substituted AMP derivatives were synthesized and investigated. Certain 2-substituted AMP derivatives, including 2-hexylthio-AMP, 2-cyclopentylthio-AMP, 2-cyclohexylmethylthio-AMP, and 2-cyclohexylethylthio-AMP were accepted as substrates by ecto-5′-NT and readily converted to the corresponding 2-substituted adenosine derivatives. The 2-cyclohexylethylthio substitution was a good compromise between the requirements of the ecto-5′-NT and the adenosine A2A receptor. The corresponding AMP derivative (12g) was a similarly good substrate as AMP itself, while the resulting adenosine derivative (11g) was a relatively potent A2A agonist (radioligand binding to rat brain striatal membranes: Ki=372 nM; inhibition of anti-CD3/anti-CD28-induced IFN-γ release in mouse CD4+ cells: EC50=50 nM). Compound 11g was released from 12g by incubation with CD4+ cells isolated from wild-type mice but only to a much smaller extent by cells from ecto-5′-NT knockout mice. Compound 12g will be a new lead structure for the development of more potent and selective ecto-5′-NT- activated prodrugs of selective anti-inflammatory A2A receptor agonists.
