1190306-10-5Relevant academic research and scientific papers
Exploring the 2- and 5-positions of the pyrazolo[4,3-d]pyrimidin-7-amino scaffold to target human A1 and A2A adenosine receptors
Squarcialupi, Lucia,Falsini, Matteo,Catarzi, Daniela,Varano, Flavia,Betti, Marco,Varani, Katia,Vincenzi, Fabrizio,Dal Ben, Diego,Lambertucci, Catia,Volpini, Rosaria,Colotta, Vittoria
, p. 2794 - 2808 (2016/06/08)
A new series of 7-aminopyrazolo[4,3-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.
2-Arylpyrazolo[4,3-d]pyrimidin-7-amino derivatives as new potent and selective human A3 adenosine receptor antagonists. Molecular modeling studies and pharmacological evaluation
Squarcialupi, Lucia,Colotta, Vittoria,Catarzi, Daniela,Varano, Flavia,Filacchioni, Guido,Varani, Katia,Corciulo, Carmen,Vincenzi, Fabrizio,Borea, Pier Andrea,Ghelardini, Carla,Di Cesare Mannelli, Lorenzo,Ciancetta, Antonella,Moro, Stefano
, p. 2256 - 2269 (2013/05/21)
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-Phenylpyrazolo[4,3-d]pyrimidin-7-one as a new scaffold to obtain potent and selective human a3 adenosine receptor antagonists: new insights into the receptor-antagonist recognition
Lenzi, Ombretta,Colotta, Vittoria,Catarzi, Daniela,Varano, Flavia,Poli, Daniela,Filacchioni, Guido,Varani, Katia,Vincenzi, Fabrizio,Borea, Pier Andrea,Paoletta, Silvia,Morizzo, Erika,Moro, Stefano
experimental part, p. 7640 - 7652 (2010/08/03)
A molecular simplification approach of previously reported 2-arylpyrazolo[3,4-c]quinolin-4-ones was applied to design 2-arylpyrazolo[4,3-d] pyrimidin-7-one derivatives as new human A3 adenosine receptor antagonists. Substituents with different
