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.
56
2256
2269
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
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/2158/805071
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