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Potent, Metabolically Stable 2‐Alkyl‐8‐(2 H ‐1,2,3‐triazol‐2‐yl)‐9 H ‐adenines as Adenosine A 2A Receptor Ligands
Author(s) -
Pace Silvia,
Brogin Giandomenico,
Stasi Maria Antonietta,
Riccioni Teresa,
Borsini Franco,
Capocasa Francesca,
Manera Francesco,
Tallarico Carlo,
Grossi Pietro,
Vacondio Federica,
Bassi Michele,
Bartoccini Francesca,
Lucarini Simone,
Piersanti Giovanni,
Tarzia Giorgio,
Cabri Walter,
Minetti Patrizia
Publication year - 2015
Publication title -
chemmedchem
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.817
H-Index - 100
eISSN - 1860-7187
pISSN - 1860-7179
DOI - 10.1002/cmdc.201500113
Subject(s) - chemistry , stereochemistry , ic50 , microsome , adenosine , amine gas treating , purine metabolism , metabolism , receptor , purine , in vitro , alkyl , biochemistry , enzyme , organic chemistry
Inhibition of adenosine A 2A receptors has been shown to elicit a therapeutic response in preclinical animal models of Parkinson’s disease (PD). We previously identified the triazolo‐9 H ‐purine, ST1535, as a potent A 2A R antagonist. Studies revealed that ST1535 is extensively hydroxylated at the ω‐1 position of the butyl side chain. Here, we describe the synthesis and evaluation of derivatives in which the ω‐1 position has been substituted (F, Me, OH) in order to block metabolism. The stability of the compounds was evaluated in human liver microsomes (HLM), and the affinity for A 2A R was determined. Two compounds, (2‐(3,3‐dimethylbutyl)‐9‐methyl‐8‐(2 H ‐1,2,3‐triazol‐2‐yl)‐9 H ‐purin‐6‐amine ( 3 b ) and 4‐(6‐amino‐9‐methyl‐8‐(2 H ‐1,2,3‐triazol‐2‐yl)‐9 H ‐purin‐2‐yl)‐2‐methylbutan‐2‐ol ( 3 c ), exhibited good affinity against A 2A R ( K i =0.4 n M and 2 n M , respectively) and high in vitro metabolic stability (89.5 % and 95.3 % recovery, respectively, after incubation with HLM for two hours).