title: A facile and novel synthesis of N(2)-, C(6)-substituted pyrazolo[3,4-d]pyrimidine-4 carboxylate derivatives as adenosine receptor antagonists.
abstract: 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.
authors: Department of Pharmacy, National University of Singapore, 3 Science Drive 2, Singapore 117543, Singapore.
authors: G
authors: G
authors: Venkatesan
authors: Pharmaceutical Chemistry Division, School of Advance Science, Vellore Institute of Technology University, Vellore 632014, Tamilnadu, India.
authors: P
authors: P
authors: Paira
authors: Department of Pharmacy, National University of Singapore, 3 Science Drive 2, Singapore 117543, Singapore.
authors: S L
authors: SL
authors: Cheong
authors: Dipartimento di Scienze Chimiche e Farmaceutiche, Università degli Studi di Trieste, Piazzale Europa 1, Trieste 34128, Italy.
authors: S
authors: S
authors: Federico
authors: Institut für Pharmakologie und Toxikologie, Universität Würzburg, Versbacher Strasse 9, Würzburg 97078, Germany.
authors: K N
authors: KN
authors: Klotz
authors: Dipartimento di Scienze Chimiche e Farmaceutiche, Università degli Studi di Trieste, Piazzale Europa 1, Trieste 34128, Italy.
authors: G
authors: G
authors: Spalluto
authors: Department of Pharmacy, National University of Singapore, 3 Science Drive 2, Singapore 117543, Singapore. Electronic address: phapg@nus.edu.sg.
authors: G
authors: G
authors: Pastorin
mesh_terms: D058918:Adenosine A3 Receptor Antagonists / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D008024:Ligands; D008958:Models, Molecular; D015394:Molecular Structure; D011720:Pyrazoles / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D011743:Pyrimidines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D043684:Receptor, Adenosine A3 / Q000378:metabolism*; D013329:Structure-Activity Relationship
chemical_list: D058918:Adenosine A3 Receptor Antagonists; D008024:Ligands; D011720:Pyrazoles; D011743:Pyrimidines; D043684:Receptor, Adenosine A3
keywords: Adenosine receptor antagonists; Carboxylate derivatives; Homology modeling; Molecular docking; Pyrazolo[3,4-d]pyrimidine; Structure-affinity relationship