New 8-amino-1,2,4-triazolo[4,3-a]pyrazin-3-one derivatives. Evaluation of different moieties on the 6-aryl ring to obtain potent and selective human A2A adenosine receptor antagonists |
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| Affiliation: | 1. Dipartimento di Neuroscienze, Psicologia, Area del Farmaco e Salute del Bambino, Sezione di Farmaceutica e Nutraceutica, Università degli Studi di Firenze, Via Ugo Schiff, 6, 50019 Sesto Fiorentino, Italy;2. Scuola di Scienze del Farmaco e dei Prodotti della Salute, Università degli Studi di Camerino, Via S. Agostino 1, 62032 Camerino, MC, Italy;1. Department of Technology and Biotechnology of Drugs Jagiellonian University Medical College, Medyczna 9, PL 30-688 Kraków, Poland;2. PharmaCenter Bonn, Pharmaceutical Institute, Pharmaceutical Chemistry I, University of Bonn, An der Immenburg 4, 53121 Bonn, Germany;3. Institute of General and Ecological Chemistry, Technical University of Łódź, Żwirki 36, 90-924 Łódź, Poland;1. PharmaCenter Bonn, Pharmaceutical Institute, Pharmaceutical Chemistry I, University of Bonn, An der Immenburg 4, 53121 Bonn, Germany;2. CNS Research, Medicinal Chemistry & Lead Generation, UCB S.A., Chemin du Foriest, 1420 Braine l’Alleud, Belgium;1. Dipartimento di Scienze Chimiche e Farmaceutiche, Università Degli Studi di Trieste, Via Licio Giorgeri 1, 34127, Trieste, Italy;2. Molecular Modeling Section (MMS), Dipartimento di Scienze Del Farmaco, Università di Padova, Via Marzolo 5, 35131, Padova, Italy;3. Laboratory of Bioorganic Chemistry, NIDDK, National Institute of Health, Bethesda, MD, USA;1. Pharmaceutical Institute, Department of Pharmaceutical & Medicinal Chemistry, University of Bonn, An der Immenburg 4, D-53121, Bonn, Germany;2. Pharma Center Bonn, University of Bonn, Brühlerstr. 7, D-53121, Bonn, Germany;3. Department of Medicinal Chemistry, B. V. Patel Pharmaceutical Education and Research Development (PERD) Centre, Ahmedabad, 380 054, Gujarat, India;1. Department of Medicinal Chemistry, B. V. Patel Pharmaceutical Education and Research Development (PERD) Centre, Sarkhej-Gandhinagar Highway, Thaltej, Ahmedabad 380 054, Gujarat, India;2. Institut für Pharmakologie und Toxikologie, Julius-Maximilians-Universität Würzburg, Germany |
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| Abstract: | In this work, further structural investigations on the 8-amino-2-phenyl-6-aryl-1,2,4-triazolo[4,3-a]pyrazin-3-one series were carried out to achieve potent and selective human A2A adenosine receptor (AR) antagonists. Different ether and amide moieties were attached at the para-position of the 6-phenyl ring, thus leading to compounds 1–9 and 10–18, respectively. Most of these moieties contained terminal basic rings (pyrrolidine, morpholine, piperidine and substituted piperazines) which were thought to confer good physicochemical and drug-like properties.Compounds 11–16, bearing the amide linker, possessed high affinity and selectivity for the hA2A AR (Ki = 3.6–11.8 nM). Also derivatives 1–9, featuring an ether linker, preferentially targeted the hA2A AR but with lower affinity, compared to those of the relative amide compounds. Docking studies, carried out at the hA2A AR binding site, highlighted some crucial ligand-receptor interactions, particularly those provided by the appended substituent whose nature deeply affected hA2A AR affinity. |
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| Keywords: | G protein-coupled receptors Ligand-adenosine receptor modeling studies |
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