Exploring the 2- and 5-positions of the pyrazolo[4,3-d]pyrimidin-7-amino scaffold to target human A1 and A2A adenosine receptors |
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| Institution: | 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. Dipartimento di Scienze Mediche, Sezione di Farmacologia, Università degli Studi di Ferrara, Via Fossato di Mortara 17-19, 44121 Ferrara, Italy;3. Scuola di Scienze del Farmaco e dei Prodotti della Salute, Università degli Studi di Camerino, via S.Agostino 1, 62032 Camerino (MC), Italy;1. Molecular Recognition Section, Laboratory of Bioorganic Chemistry, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD 20892-0810, USA;2. Department of Pharmacological and Physiological Science, Saint Louis University School of Medicine, St. Louis, MO 63104, USA;1. Phenex Pharmaceuticals AG, Waldhofer Strasse 104, 69123 Heidelberg, Germany;2. Janssen Research and Development, Spring House, PA 19477, USA;3. Janssen Research and Development, LLC, San Diego, CA 92121, USA;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. 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 ?ód?, ?wirki 36, 90-924 ?ód?, Poland;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;1. Dipartimento NEUROFARBA, Sezione Farmaceutica e Nutraceutica, Università degli Studi di Firenze, Via Ugo Schiff 6, 50019 Sesto Fiorentino, Italy;2. Department of Chemistry, Imperial College London, South Kensington, London SW7 2AZ, UK;3. Dipartimento di Farmacia, Università degli Studi di Pisa, Via Bonanno 6, 56126 Pisa, Italy;4. NEUROFARBA, Sezione Farmacologia e Tossicologia, Università degli Studi di Firenze, Viale Pieraccini 6, 50139 Firenze, Italy |
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| Abstract: | A new series of 7-aminopyrazolo4,3-d]pyrimidine derivatives (1–31) were synthesized to evaluate some structural modifications at the 2- and 5-positions aimed at shifting affinity towards the human (h) A2A adenosine receptor (AR) or both hA2A and hA1 ARs. The most active compounds were those featured by a 2-furyl or 5-methylfuran-2-yl moiety at position 5, combined with a benzyl or a substituted-benzyl group at position 2. Several of these derivatives (22–31) displayed nanomolar affinity for the hA2A AR (Ki = 3.62–57 nM) and slightly lower for the hA1 ARs, thus showing different degrees (3–22 fold) of hA2A versus hA1 selectivity. In particular, the 2-(2-methoxybenzyl)-5-(5-methylfuran-2-yl) derivative 25 possessed the highest hA2A and hA1 AR affinities (Ki = 3.62 nM and 18 nM, respectively) and behaved as potent antagonist at both these receptors (cAMP assays). Its 2-(2-hydroxybenzyl) analog 26 also showed a high affinity for the hA2A AR (Ki = 5.26 nM) and was 22-fold selective versus the hA1 subtype. Molecular docking investigations performed at the hA2A AR crystal structure and at a homology model of the hA1 AR allowed us to represent the hypothetical binding mode of our derivatives and to rationalize the observed SARs. |
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| Keywords: | G protein-coupled receptors Ligand–adenosine receptor modeling studies |
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