Potent, Metabolically Stable 2‐Alkyl‐8‐(2H‐1, 2, 3‐triazol‐2‐yl)‐9H‐adenines as Adenosine A2A Receptor Ligands. Issue 7 (7th May 2015)

• Record Type: Journal Article
• Authors: 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
• Is Part Of: ChemMedChem. Volume 10:Issue 7(2015:Jul.)
• Page Start: 1149
• Page End: 1152
• Publication Date: 2015-05-07
• Subjects: Pharmaceutical chemistry -- Periodicals; 615.19005
• DOI: 10.1002/cmdc.201500113
• Languages: English
• ISSNs: 1860-7179

Abstract

<abstract abstract-type="main" xml:lang="en"> <title>Abstract</title> <p>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<italic>H</italic>‐purine, ST1535, as a potent A_2AR 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_2AR was determined. Two compounds, (2‐(3, 3‐dimethylbutyl)‐9‐methyl‐8‐(2<italic>H</italic>‐1, 2, 3‐triazol‐2‐yl)‐9<italic>H</italic>‐purin‐6‐amine (<bold>3 b</bold>) and 4‐(6‐amino‐9‐methyl‐8‐(2<italic>H</italic>‐1, 2, 3‐triazol‐2‐yl)‐9<italic>H</italic>‐purin‐2‐yl)‐2‐methylbutan‐2‐ol (<bold>3 c</bold>), exhibited good affinity against A_2AR (<italic>K</italic>_i=0.4 n<sc>M</sc> and 2 n<sc>M</sc>, respectively) and high in vitro metabolic stability (89.5 % and 95.3 % recovery, respectively, after incubation with HLM for two hours).</p> </abstract>