Nucleoside-5'-monophosphates as prodrugs of adenosine A2A receptor agonists activated by ecto-5'-nucleotidase.
Prodrugs of adenosine A(2A) 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 A(2A) 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 A(2A) receptor. The corresponding AMP derivative (12g) was a similarly good substrate as AMP itself, while the resulting adenosine derivative (11g) was a relatively potent A(2A) agonist (radioligand binding to rat brain striatal membranes: K(i) = 372 nM; inhibition of anti-CD3/anti-CD28-induced IFN-gamma release in mouse CD4+ cells: EC(50) = 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 A(2A) receptor agonists.
El-Tayeb
Ali
A
PharmaCenter Bonn, Pharmaceutical Institute, Pharmaceutical Chemistry I, University of Bonn, An der Immenburg 4, D-53121 Bonn, Germany.
Iqbal
Jamshed
J
Behrenswerth
Andrea
A
Romio
Michael
M
Schneider
Marion
M
Zimmermann
Herbert
H
Schrader
Jürgen
J
Müller
Christa E
CE
D015720:5'-Nucleotidase / Q000378:metabolism*; D058908:Adenosine A2 Receptor Agonists; D000249:Adenosine Monophosphate / Q000737:chemistry / Q000378:metabolism*; D000818:Animals; D000893:Anti-Inflammatory Agents / Q000009:adverse effects / Q000378:metabolism / Q000494:pharmacology; D015971:Gene Expression Regulation, Enzymologic; D006801:Humans; D006868:Hydrolysis; D007371:Interferon-gamma / Q000096:biosynthesis; D008297:Male; D051379:Mice; D011355:Prodrugs / Q000737:chemistry / Q000378:metabolism*; D051381:Rats; D013601:T-Lymphocytes / Q000187:drug effects / Q000378:metabolism; D014664:Vasodilation / Q000187:drug effects
D058908:Adenosine A2 Receptor Agonists; D000893:Anti-Inflammatory Agents; D011355:Prodrugs; D000249:Adenosine Monophosphate; D007371:Interferon-gamma; D015720:5'-Nucleotidase