Scaffold decoration at positions 5 and 8 of 1,2,4-triazolo[1,5-c]pyrimidines to explore the antagonist profiling on adenosine receptors: a preliminary structure-activity relationship study
| Autor: | Stefano Moro, Giorgia Pastorin, Stephanie Federico, Sara Redenti, Antonella Ciancetta, Giampiero Spalluto, Karl-Norbert Klotz, Nicola Porta, Barbara Cacciari |
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| Přispěvatelé: | Federico, Stephanie, Ciancetta, Antonella, Porta, Nicola, Redenti, Sara, Pastorin, Giorgia, Cacciari, Barbara, Klotz, Karl Norbert, Moro, Stefano, Spalluto, Giampiero |
| Rok vydání: | 2014 |
| Předmět: |
Models
Molecular Scaffold Pyrimidine Receptor Adenosine A2A Stereochemistry In silico NO Dose-Response Relationship Binding profile chemistry.chemical_compound Adenosine A2A Structure-Activity Relationship Models Drug Discovery Molecule Structure–activity relationship Dose-Response Relationship Drug Humans Molecular Structure Purinergic P1 Receptor Antagonists Pyrimidines Receptor Adenosine A3 Triazoles Molecular Medicine Drug Discovery3003 Pharmaceutical Science Antagonist Molecular Adenosine receptor chemistry Adenosine A3 Purinergic P1 Receptor Antagonist Triazole Drug Human Receptor |
| Zdroj: | Journal of medicinal chemistry. 57(14) |
| ISSN: | 1520-4804 |
| Popis: | The structure–activity relationship (SAR) of new 5,8-disubstituted-1,2,4-triazolo[1,5-c]pyrimidines as adenosine receptors (ARs) antagonists has been explored. All the synthesized compounds show affinity for the hA2A and hA3 ARs depending on the substitution patterns at the 5 and 8 positions. In particular, a free amino group at the 5 position with an ethoxycarbonyl group at the 8 position leads to potent and quite selective hA2A antagonists (compound 12: hA2A AR Ki = 3.32 nM; hA1/hA2A = 55.6; hA2A/hA3 = 0.01), whereas the introduction of a methylamino function at the 5 position yields a good binding profile at the hA3 AR (compound 23: hA3 AR Ki = 4.14 nM, hA1/hA3 = 236; hA2A/hA3 = 25). Through an in silico receptor-driven approach, we have determined the most favorable orientation of the substitutions at the 5 and 8 positions of the 1,2,4-triazolo[1,5-c]pyrimidine (TP) scaffold and, accordingly, we have elucidated the observed SAR. |
| Databáze: | OpenAIRE |
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