159979-72-3Relevant academic research and scientific papers
A facile and novel synthesis of N2-, C6-substituted pyrazolo[3,4- d ]pyrimidine-4 carboxylate derivatives as adenosine receptor antagonists
Venkatesan,Paira,Cheong,Federico,Klotz,Spalluto,Pastorin
, p. 784 - 798 (2015)
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 t
Discovery of simplified N2-substituted pyrazolo[3,4-d]pyrimidine derivatives as novel adenosine receptor antagonists: Efficient synthetic approaches, biological evaluations and molecular docking studies
Venkatesan, Gopalakrishnan,Paira, Priyankar,Cheong, Siew Lee,Vamsikrishna, Kosaraju,Federico, Stephanie,Klotz, Karl-Norbert,Spalluto, Giampiero,Pastorin, Giorgia
, p. 1751 - 1765 (2014/03/21)
In the present study, a molecular simplification approach was employed to design novel bicyclic pyrazolo[3,4-d]pyrimidine (PP) derivatives from tricyclic pyrazolo[4,3-e]-1,2,4-triazolo-[1,5-c]pyrimidines (PTP) as promising human A3 adenosine receptor (hA3AR) antagonists. All the target compounds were synthesized using novel and efficient synthetic schemes and the structure-activity relationship studies of these PPs were explored through the synthesis of a series of PTP analogues with various substituents. Substituents with different lipophilicity and steric hindrance (e.g., alkyl and aryl-alkyl) functions were introduced at N2 position of the pyrazole ring, while acyl groups with different electronic properties were introduced at C 6 position of the bicyclic nucleus to probe both electronic and positional effects. Most of the synthesized derivatives of the PP series presented good affinity at the hA3AR, as indicated by the low micromolar range of Ki values and among them, compound 63 with N 2 neopentyl substituents showed most potent hA3AR affinity with Ki value of 0.9 μM and high selectivity (hA 1AR/hA3AR = >111 & hA2AAR/hA 3AR = >111) towards other adenosine receptor subtypes. Interestingly, small isopropyl groups at N2 position displayed high affinity at another receptor subtype (hA2AAR, e.g., compound 55, with Ki hA2AAR = 0.8 μM), while they were less favorable at the hA3AR. Molecular docking analysis was also performed to predict the possible binding mode of target compounds inside the hA3AR and hA2AAR. Overall, PP derivatives represent promising starting points for new AR antagonists.
Organoruthenium antagonists of human A3 adenosine receptors
Paira, Priyankar,Chow, Mun Juinn,Venkatesan, Gopalakrishnan,Kosaraju, Vamsi Krishna,Cheong, Siew Lee,Klotz, Karl-Norbert,Ang, Wee Han,Pastorin, Giorgia
, p. 8321 - 8330 (2013/07/27)
Human A3 adenosine receptor (hA3AR) is a membrane-bound G protein-coupled receptor implicated in a number of severe pathological conditions, including cancer, in which it acts as a potential therapeutic target. To derive structure-activity relationships on pyrazolo-triazolo-pyrimidine (PTP)-based A3AR antagonists, we developed a new class of organometallic inhibitors through replacement of the triazolo moiety with an organoruthenium fragment. The objective was to introduce by design structural diversity into the PTP scaffold in order to tune their binding efficacy toward the target receptor. These novel organoruthenium antagonists displayed good aquatic stability and moderate binding affinity toward the hA3 receptor in the low micromolar range. The assembly of these complexes through a template-driven approach with selective ligand replacement at the metal center to control their steric and receptor-binding properties is discussed. Scaffold design: A novel class of ruthenium(II)-arene complexes containing chelating N,N-pyrazolo-pyrimidine ligands was rationally developed to be selective antagonists of human A3 adenosine receptors based on the proven pyrazolo-triazolo-pyrimidine design (see figure). Copyright
Does the combination of optimal substitutions at the C2-, N 5- and N8-positions of the pyrazolo-triazolo-pyrimidine scaffold guarantee selective modulation of the human A3 adenosine receptors?
Cheong, Siew Lee,Dolzhenko, Anton V.,Paoletta, Silvia,Lee, Evelyn Pei Rong,Kachler, Sonja,Federico, Stephanie,Klotz, Karl-Norbert,Dolzhenko, Anna V.,Spalluto, Giampiero,Moro, Stefano,Pastorin, Giorgia
scheme or table, p. 6120 - 6134 (2011/11/07)
In an attempt to study the optimal combination of a phenyl ring at the C2-position and different substituents at the N5- and N8-positions towards the selective modulation of human A3 adenosine receptors (hA3AR), we synthesized a new series of 2-para-(un)substituted-phenyl-pyrazolo-triazolo-pyrimidines bearing either a methyl or phenylethyl at N8 and chains of variable length at N 5. Through biological evaluation, it was found that the majority of the compounds had good affinities towards the hA3AR in the low nanomolar range. Compound 16 possessed the best hA3AR affinity and selectivity profile (KihA3 = 1.33 nM; hA 1/hA3 = 4880; hA2A/hA3 = 1100) in the present series of 2-(substituted)phenyl-pyrazolo-triazolo-pyrimidine derivatives. In addition to pharmacological characterization, a molecular modeling investigation on these compounds further elucidated the effect of different substituents at the pyrazolo-triazolo-pyrimidine scaffold on affinity and selectivity to hA3AR.
Novel, highly potent adenosine deaminase inhibitors containing the pyrazolo[3,4-d]pyrimidine ring system. Synthesis, structure-activity relationships, and molecular modeling studies
Da Settimo, Federico,Primofiore, Giampaolo,La Motta, Concettina,Taliani, Sabrina,Simorini, Francesca,Marini, Anna Maria,Mugnaini, Laura,Lavecchia, Antonio,Novellino, Ettore,Tuscano, Daniela,Martini, Claudia
, p. 5162 - 5174 (2007/10/03)
This study reports the synthesis of a number of 1- and 2-alkyl derivatives of the 4-aminopyrazolo[3,4-d]pyrimidine (APP) nucleus and their evaluation as inhibitors of ADA from bovine spleen. The 2-substituted aminopyrazolopyrimidines proved to be potent inhibitors, most of them exhibiting Ki values in the nanomolar/subnanomolar range. In this series the inhibitory activity is enhanced with the increase in length of the alkyl chain, reaching a maximum with the n-decyl substituent. Insertion of a 2′-hydroxy group in the ra-decyl chain gave 3k, whose (R)-isomer displayed the highest inhibitory potency of the series (Ki 0.053 nM), showing an activity 2 orders of magnitude higher than that of (+)-EHNA (Ki 1.14 nM), which was taken as the reference standard. Docking simulations of aminopyrazolopyrimidines into the ADA binding site were also performed, to rationalize the structure-activity relationships of this class of inhibitors.
Pyrazolo[4,3-e]-1,2,4-triazolo[1,5-c]pyrimidine derivatives: Potent and selective A2A adenosine antagonists
Baraldi, Pier Giovanni,Cacciari, Barbara,Spalluto, Giampiero,Pineda De Las Infantas Y Villatoro, Maria José,Zocchi, Cristina,Dionisotti, Silvio,Ongini, Ennio
, p. 1164 - 1171 (2007/10/03)
A series of pyrazolo[4,3-e]-1,2,4-triazolo[1,5-c]pyrimidine derivatives (10a-o,q,r), bearing alkyl and aralkyl chains on positions 7 and 8, were synthesized in the attempt to obtain potent and selective antagonists for the A2A adenosine receptor subtype. The compounds were tested in binding and functional assays to evaluate their potency for the A2A compared with the A1 adenosine receptor subtype. In binding studies in rat brain membranes, most of the compounds showed affinity for A2A receptors in the low nanomolar range with a different degree of A2A versus A1 selectivity. Comparison of N7 (10a-d,h-o)- and N8 (10e-g)-substituted pyrazolo derivatives indicates that N7 substitution decreases the A1 affinity with the concomitant increase of A2A selectivity. Specifically, the introduction of a 3-phenylpropyl group at pyrazolo nitrogen in position 7 (101) increased significantly the A2A selectivity, being 210-fold, while the A2A receptor affinity remained high (Ki = 2.4 nM). With regards to the affinity for A2A receptors, also the compound 10n, bearing in the 7-position a β-morpholin-4-ylethyl group, deserves attention (K1 = 5.6 nM) even though the A2A selectivity (84-fold) was not as high as that of 101. Conversely, the compound 10m (N7-4-phenylbutyl derivative) showed a remarkable selectivity (A1/A2A ratio = 129) associated with lower A2A affinity (K1 = 21 nM). In functional studies, most of the compounds examined reversed 5′-(N-ethylcarbamoyl)adenosine-induced inhibition of rabbit platelet aggregation inhibition which is a biological response mediated by the A2A receptor subtype. The compounds are potent and selective A2A antagonists which can be useful to elucidate the pathophysiological role of this adenosine receptor subtype. These compounds deserve to be further developed to assess their potential for treatment of neurodegenerative disorders such as Parkinson's disease.
