A facile and novel synthesis of N(2)-, C(6)-substituted pyrazolo[3,4-d]pyrimidine-4 carboxylate derivatives as adenosine receptor antagonists

• Published in: European journal of medicinal chemistry 2015-03, Vol.92, p.784-798
• Main Authors: Venkatesan, G, Paira, P, Cheong, S L, Federico, S, Klotz, K N, Spalluto, G, Pastorin, G
• Format: Article
• Language: English
• Subjects: Adenosine A3 Receptor Antagonists - chemical synthesis; Adenosine A3 Receptor Antagonists - chemistry; Adenosine A3 Receptor Antagonists - pharmacology; Humans; Ligands; Models, Molecular; Molecular Structure; Pyrazoles - chemical synthesis; Pyrazoles - chemistry; Pyrazoles - pharmacology; Pyrimidines - chemical synthesis; Pyrimidines - chemistry; Pyrimidines - pharmacology; Receptor, Adenosine A3 - metabolism; Structure-Activity Relationship
• ISSN: 1768-3254
• DOI: 10.1016/j.ejmech.2015.01.046

An efficient synthetic procedure was adopted to synthesize a series of new molecules containing the pyrazolo[3,4-d]pyrimidine (PP) scaffold, which have been evaluated as promising human adenosine receptor (AR) antagonists. The effect of substitutions at the N(2), C(4) and C(6) positions of PPs on the affinity and selectivity towards the adenosine receptors were explored. Most of the pyrazolo[3,4-d]pyrimidine-4-carboxylates displayed from moderate to good affinity at the human A3AR (hA3AR), as indicated by the low micromolar range of Ki values (Ki hA3AR = 0.7-34 μM). In particular, compounds 60 and 62 displayed good affinity at the hA3AR (60, Ki hA3AR = 2.2 μM and 62, Ki hA3AR = 2.9 μM) and selectivity towards the other AR subtypes (60, >46-fold selective and 62, >34-fold selective, respectively). In view of these results, these novel PP analogues were docked both in the crystallographic structure of the hA2AAR and in a homology model of the hA3AR in order to support the structure activity relationship (SAR) analysis. These preliminary results demonstrated that pyrazolo[3,4-d]pyrimidine can be considered a promising scaffold to obtain new molecules with potent hA3AR antagonist activity.