646512-00-7Relevant academic research and scientific papers
Pharmacophore based receptor modeling: The case of adenosine A3 receptor antagonists. An approach to the optimization of protein models
Tafi, Andrea,Bernardini, Cesare,Botta, Maurizio,Corelli, Federico,Andreini, Matteo,Martinelli, Adriano,Ortore, Gabriella,Baraldi, Pier Giovanni,Fruttarolo, Francesca,Borea, Pier Andrea,Tuccinardi, Tiziano
, p. 4085 - 4097 (2007/10/03)
To design and synthesize new potent and selective antagonists of the human A3 adenosine receptor, pharmacophoric hypotheses were generated with the software Catalyst for a comprehensive set of compounds retrieved from previous literature. Three of these pharmacophores were used to drive the optimization of a molecular model of the receptor built by homology modeling. The alignment of the ligands proposed by Catalyst was then used to manually dock a set of known A3 antagonists into the binding site, and as a result, the model was able to explain the different binding mode of very active compounds with respect to less active ones and to reproduce, with good accuracy, free energies of binding. The docking highlighted that the nonconserved residue Tyr254 could play an important role for A3 selectivity, suggesting that a mutagenesis study on this residue could be of interest in this respect. The reliability of the whole approach was successfully tested by rational design and synthesis of new compounds.
New strategies for the synthesis of A3 adenosine receptor antagonists
Baraldi, Pier Giovanni,Bovero, Andrea,Fruttarolo, Francesca,Romagnoli, Romeo,Tabrizi, Mojgan Aghazadeh,Preti, Delia,Varani, Katia,Borea, Pier Andrea,Moorman, Allan R.
, p. 4161 - 4169 (2007/10/03)
New A3 adenosine receptor antagonists were synthesized and tested at human adenosine receptor subtypes. An advanced synthetic strategy permitted us to obtain a large amount of the key intermediate 5 that was then submitted to alkylation procedures in order to obtain the derivatives 6-8. These compounds were then functionalised into ureas at the 5-position (compounds 9-11, 18 and 19) to evaluate their affinity and selectivity versus hA3 adenosine receptor subtype; in particular, compounds 18 and 19 displayed a value of affinity of 4.9 and 1.3 nM, respectively. Starting from 5, the synthetic methodologies employed permitted us to perform a rapid and a convenient divergent synthesis. A further improvement allowed the regioselective preparation of the N8-substituted compound 7. This method could be used as an helpful general procedure for the design of novel A3 adenosine receptor antagonists without the difficulty of separating the N8-substituted pyrazolo[4,3-e]1,2,4-triazolo[1,5-c]pyrimidines from the corresponding N 7-isomers.
