Nucleoside-5′-monophosphates as Prodrugs of Adenosine A2A Receptor Agonists Activated by ecto-5′-Nucleotidase†Contribution to celebrate the 100th anniversary of the Division of Medicinal Chemistry of the American Chemical Society
| Autor: | Schrader J, Michael Romio, Christa E. Müller, Jamshed Iqbal, Herbert Zimmermann, Andrea Behrenswerth, Ali El-Tayeb, Marion Schneider |
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| Rok vydání: | 2009 |
| Předmět: | |
| Zdroj: | Journal of Medicinal Chemistry. 52:7669-7677 |
| ISSN: | 1520-4804 0022-2623 |
| DOI: | 10.1021/jm900538v |
| Popis: | 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-CD... |
| Databáze: | OpenAIRE |
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