Exploiting the Pyrazolo[3,4-d]pyrimidin-4-one Ring System as a Useful Template To Obtain Potent Adenosine Deaminase Inhibitors
| Autor: | Concettina La Motta, Mario Del Tacca, Matteo Fornai, Francesca Simorini, Silvia Salerno, Antonio Lavecchia, Ettore Novellino, Sabrina Taliani, Federico Da Settimo, Anna Maria Marini, Corrado Blandizzi, Luca Antonioli, L. Mugnaini, Stefania Sartini |
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| Přispěvatelé: | LA MOTTA, C., Sartini, S., Mugnaini, L., Salerno, S., Simorini, F., Taliani, S., Marini, A. M., DA SETTIMO, F., Lavecchia, Antonio, Novellino, Ettore, Antonioli, L., Fornai, M., Blandizzi, C., DEL TACCA, M. |
| Rok vydání: | 2009 |
| Předmět: |
Pyridines
Stereochemistry Chemical synthesis Structure-Activity Relationship chemistry.chemical_compound Adenosine deaminase In vivo Catalytic Domain Drug Discovery Adenosine Deaminase Inhibitors Animals Structure–activity relationship Enzyme Inhibitors chemistry.chemical_classification Trifluoromethyl Dose-Response Relationship Drug biology Colitis Rats Enzyme chemistry Docking (molecular) biology.protein Pyrazoles Molecular Medicine Adenosine Deaminase Inhibitor |
| Zdroj: | Journal of Medicinal Chemistry. 52:1681-1692 |
| ISSN: | 1520-4804 0022-2623 |
| DOI: | 10.1021/jm801427r |
| Popis: | A number of pyrazolo[3,4-d]pyrimidin-4-ones bearing either alkyl or arylalkyl substituents in position 2 of the nucleus were synthesized and tested for their ability to inhibit adenosine deaminase (ADA) from bovine spleen. The 2-arylalkyl derivatives exhibited excellent inhibitory activity, showing Ki values in the nanomolar/subnanomolar range. The most active compound, 1-(4-((4-oxo-4,5-dihydropyrazolo[3,4-d]pyrimidin-2-yl)methyl)phenyl)-3-(4-(trifluoromethyl)phenyl)urea, 14d, was tested in rats with colitis induced by 2,4-dinitrobenzenesulfonic acid to assess its efficacy to attenuate bowel inflammation. The treatment with 14d induced a significant amelioration of both systemic and intestinal inflammatory alterations in animals with experimental colitis. Docking simulations of the synthesized compounds into the ADA catalytic site were also performed to rationalize the structure−activity relationships observed and to highlight the key pharmacophoric elements of these products, thus prospectively guiding the design of novel ADA inhibitors. |
| Databáze: | OpenAIRE |
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