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Synthesis and Biological Evaluation of Metabolites of 2-n-Butyl-9-methyl-8-[1,2,3]triazol-2-yl-9H-purin-6-ylamine (ST1535), A Potent Antagonist of the A2A Adenosine Receptor for the Treatment of Parkinson’s Disease

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† Dipartimento di Scienze Biomolecolari, Università degli Studi di Urbino, Piazza Rinascimento 6, I-61029 Urbino (PU), Italy
‡ Sigma-Tau Industrie Farmaceutiche Riunite S.p.A., Via Pontina Km 30,400, I-00040 Pomezia, Italy
*For G.P.: phone, +390722303320; fax, +390722303313; E-mail, [email protected]. For P.M.: E-mail, [email protected]
Cite this: J. Med. Chem. 2013, 56, 13, 5456–5463
Publication Date (Web):June 12, 2013
https://doi.org/10.1021/jm400491x
Copyright © 2013 American Chemical Society
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    Abstract

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    The synthesis and preliminary in vitro evaluation of five metabolites of the A2A antagonist ST1535 (1) are reported. The metabolites, originating in vivo from enzymatic oxidation of the 2-butyl group of the parent compound, were synthesized from 6-chloro-2-iodo-9-methyl-9H-purine (2) by selective C–C bond formation via halogen/magnesium exchange reaction and/or palladium-catalyzed reactions. The metabolites behaved in vitro as antagonist ligands of cloned human A2A receptor with affinities (Ki 7.5–53 nM) comparable to that of compound 1 (Ki 10.7 nM), thus showing that the long duration of action of 1 could be in part due to its metabolites. General behavior after oral administration in mice was also analyzed.

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    Copies of 1H NMR and 13C NMR spectra for compounds 3–18. Copies of HPLC chromatogram for compounds 16a–c. Irwin test of compounds 14, 16a, and 18. Binding profile for compound 14, 16a, 17, and 18. This material is available free of charge via the Internet at http://pubs.acs.org.

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    2. Ali Jazayeri, Stephen P. Andrews, and Fiona H. Marshall . Structurally Enabled Discovery of Adenosine A2A Receptor Antagonists. Chemical Reviews 2017, 117 (1) , 21-37. https://doi.org/10.1021/acs.chemrev.6b00119
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    5. Andrea Spinaci, Michela Buccioni, Cui Chang, Diego Dal Ben, Beatrice Francucci, Catia Lambertucci, Rosaria Volpini, Gabriella Marucci. Adenosine A2A Receptor Antagonists: Chemistry, SARs, and Therapeutic Potential. 2023, 101-141. https://doi.org/10.1007/7355_2023_162
    6. Catia Lambertucci, Gabriella Marucci, Daniela Catarzi, Vittoria Colotta, Beatrice Francucci, Andrea Spinaci, Flavia Varano, Rosaria Volpini. A2A Adenosine Receptor Antagonists and their Potential in Neurological Disorders. Current Medicinal Chemistry 2022, 29 (28) , 4780-4795. https://doi.org/10.2174/0929867329666220218094501
    7. Emmanuelle Pourcher, Philippe Huot. Adenosine 2A Receptor Antagonists for the Treatment of Motor Symptoms in Parkinson's Disease. Movement Disorders Clinical Practice 2015, 2 (4) , 331-340. https://doi.org/10.1002/mdc3.12187
    8. Maria Antonietta Stasi, Patrizia Minetti, Katia Lombardo, Teresa Riccioni, Antonio Caprioli, Mario Vertechy, Stefano Di Serio, Silvia Pace, Franco Borsini. Animal models of Parkinson׳s disease: Effects of two adenosine A2A receptor antagonists ST4206 and ST3932, metabolites of 2-n-Butyl-9-methyl-8-[1,2,3]triazol-2-yl-9H-purin-6-ylamine (ST1535). European Journal of Pharmacology 2015, 761 , 353-361. https://doi.org/10.1016/j.ejphar.2015.03.070
    9. Cornelis J Van der Schyf. Rational drug discovery design approaches for treating Parkinson’s disease. Expert Opinion on Drug Discovery 2015, 10 (7) , 713-741. https://doi.org/10.1517/17460441.2015.1041495
    10. Delia Preti, Pier Giovanni Baraldi, Allan R. Moorman, Pier Andrea Borea, Katia Varani. History and Perspectives of A 2A Adenosine Receptor Antagonists as Potential Therapeutic Agents. Medicinal Research Reviews 2015, 35 (4) , 790-848. https://doi.org/10.1002/med.21344
    11. Silvia Pace, Giandomenico Brogin, Maria Antonietta Stasi, Teresa Riccioni, Franco Borsini, Francesca Capocasa, Francesco Manera, Carlo Tallarico, Pietro Grossi, Federica Vacondio, Michele Bassi, Francesca Bartoccini, Simone Lucarini, Giovanni Piersanti, Giorgio Tarzia, Walter Cabri, Patrizia Minetti. Potent, Metabolically Stable 2‐Alkyl‐8‐(2 H ‐1,2,3‐triazol‐2‐yl)‐9 H ‐adenines as Adenosine A 2A Receptor Ligands. ChemMedChem 2015, 10 (7) , 1149-1152. https://doi.org/10.1002/cmdc.201500113
    12. Gengyang Yuan, Nicholas G Gedeon, Tanner C Jankins, Graham B Jones. Novel approaches for targeting the adenosine A 2A receptor. Expert Opinion on Drug Discovery 2015, 10 (1) , 63-80. https://doi.org/10.1517/17460441.2015.971006
    13. Annalisa Pinna. Adenosine A2A Receptor Antagonists in Parkinson’s Disease: Progress in Clinical Trials from the Newly Approved Istradefylline to Drugs in Early Development and Those Already Discontinued. CNS Drugs 2014, 28 (5) , 455-474. https://doi.org/10.1007/s40263-014-0161-7
    14. Francesca Bartoccini, Giovanni Piersanti, Silvia Armaroli, Alberto Cerri, Walter Cabri. Development of a practical and sustainable strategy for the synthesis of ST1535 by an iron-catalyzed Kumada cross-coupling reaction. Tetrahedron Letters 2014, 55 (7) , 1376-1378. https://doi.org/10.1016/j.tetlet.2014.01.030
    15. Nataliya Belskaya, Julia Subbotina, Svetlana Lesogorova. Synthesis of 2H-1,2,3-Triazoles. 2014, 51-116. https://doi.org/10.1007/7081_2014_125
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