Potent,Metabolically Stable 2‐Alkyl‐8‐(2H‐1,2,3‐triazol‐2‐yl)‐9H‐adenines as Adenosine A2A Receptor Ligands |
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| Authors: | Dr Silvia Pace Dr Giandomenico Brogin Dr Maria Antonietta Stasi Dr Teresa Riccioni Franco Borsini Dr Francesca Capocasa Dr Francesco Manera Carlo Tallarico Dr Pietro Grossi Dr Federica Vacondio Dr Michele Bassi Dr Francesca Bartoccini Dr Simone Lucarini Dr Giovanni Piersanti Prof Giorgio Tarzia Walter Cabri Dr Patrizia Minetti |
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| Affiliation: | 1. Sigma‐Tau Industrie Farmaceutiche Riunite S.p.A. Via Pontina Km?30, 400, 00040 Pomezia (Italy);2. Present addresses: Chiesi Farmaceutici S.p.A., Parma, Italy (G.B.);3. Biosint S.p.A., Sermoneta, Italy (F.C.);4. Fresenius Kabi Anti‐Infectives, Cernusco sul Naviglio, Italy (W.C.).;5. Dipartimento di Farmacia, Università degli Studi di Parma, Parco Area delle Scienze?27?A, 43124 Parma (Italy);6. Department of Biomolecular Sciences, University of Urbino, Piazza Rinascimento?6, 61029 Urbino (PU) (Italy) |
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| Abstract: | Inhibition of adenosine A2A receptors has been shown to elicit a therapeutic response in preclinical animal models of Parkinson’s disease (PD). We previously identified the triazolo‐9H‐purine, ST1535, as a potent A2AR 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 A2AR was determined. Two compounds, (2‐(3,3‐dimethylbutyl)‐9‐methyl‐8‐(2H‐1,2,3‐triazol‐2‐yl)‐9H‐purin‐6‐amine ( 3 b ) and 4‐(6‐amino‐9‐methyl‐8‐(2H‐1,2,3‐triazol‐2‐yl)‐9H‐purin‐2‐yl)‐2‐methylbutan‐2‐ol ( 3 c ), exhibited good affinity against A2AR (Ki=0.4 nM and 2 nM , respectively) and high in vitro metabolic stability (89.5 % and 95.3 % recovery, respectively, after incubation with HLM for two hours). |
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| Keywords: | adenosine A2a receptors drug discovery metabolic stability Parkinson’ s disease purines |
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