On the basis of our previously reported 2- arylpyrazolo[4,3-d]pyrimidin-7-ones, a set of 2-arylpyrazolo[4,3-d]pyrimidin-7-amines were designed as new human (h) A3 adenosine receptor (AR) antagonists. Lipophilic groups with different steric bulk were introduced at the 5-position of the bicyclic scaffold (R5 = Me, Ph, CH2Ph), and different acyl and carbamoyl moieties (R7) were appended on the 7-amino group, as well as a para-methoxy group inserted on the 2-phenyl ring. The presence of acyl groups turned out to be of paramount importance for an efficient and selective binding at the hA3 AR. In fact, most of the 7-acylamino derivatives showed low nanomolar affinity (Ki = 2.5−45 nM) and high selectivity toward this receptor. A few selected pyrazolo[4,3-d]pyrimidin-7-amides were effective in counteracting oxaliplatin-induced apoptosis in rat astrocyte cell cultures, an in vitro model of neurotoxicity. Through an in silico receptor-driven approach the obtained binding data were rationalized and the molecular bases of the observed hA3 AR affinity and hA3 versus hA2A AR selectivity were explained.
2-Arylpyrazolo[4,3-d]pyrimidin-7-amino Derivatives As New Potent and Selective Human A3Adenosine Receptor Antagonists. Molecular Modeling Studies and Pharmacological Evaluation / Lucia Squarcialupi;Vittoria Colotta;Daniela Catarzi;Flavia Varano;Guido Filacchioni;Katia Varani;Carmen Corciulo;Fabrizio Vincenzi;Pier Andrea Borea;Carla Ghelardini;Lorenzo Di Cesare Mannelli;Antonella Ciancetta;Stefano Moro. - In: JOURNAL OF MEDICINAL CHEMISTRY. - ISSN 0022-2623. - ELETTRONICO. - 56:(2013), pp. 2256-2269. [10.1021/jm400068e]
2-Arylpyrazolo[4,3-d]pyrimidin-7-amino Derivatives As New Potent and Selective Human A3Adenosine Receptor Antagonists. Molecular Modeling Studies and Pharmacological Evaluation
SQUARCIALUPI, LUCIA;COLOTTA, VITTORIA;CATARZI, DANIELA;VARANO, FLAVIA;GHELARDINI, CARLA;DI CESARE MANNELLI, LORENZO;
2013
Abstract
On the basis of our previously reported 2- arylpyrazolo[4,3-d]pyrimidin-7-ones, a set of 2-arylpyrazolo[4,3-d]pyrimidin-7-amines were designed as new human (h) A3 adenosine receptor (AR) antagonists. Lipophilic groups with different steric bulk were introduced at the 5-position of the bicyclic scaffold (R5 = Me, Ph, CH2Ph), and different acyl and carbamoyl moieties (R7) were appended on the 7-amino group, as well as a para-methoxy group inserted on the 2-phenyl ring. The presence of acyl groups turned out to be of paramount importance for an efficient and selective binding at the hA3 AR. In fact, most of the 7-acylamino derivatives showed low nanomolar affinity (Ki = 2.5−45 nM) and high selectivity toward this receptor. A few selected pyrazolo[4,3-d]pyrimidin-7-amides were effective in counteracting oxaliplatin-induced apoptosis in rat astrocyte cell cultures, an in vitro model of neurotoxicity. Through an in silico receptor-driven approach the obtained binding data were rationalized and the molecular bases of the observed hA3 AR affinity and hA3 versus hA2A AR selectivity were explained.File | Dimensione | Formato | |
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JMedChem 2013, 56, 2256.pdf
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