Exploiting the pyrazolo[3,4-d]pyrimidin-4-one ring system as a useful template to obtain potent adenosine deaminase inhibitors.

Abstract

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.

• Authors: Concettina La Motta, Stefania Sartini, Laura Mugnaini, Silvia Salerno, Francesca Simorini, Sabrina Taliani, Anna Maria Marini, Federico Da Settimo, Antonio Lavecchia, Ettore Novellino, Luca Antonioli, Matteo Fornai, Corrado Blandizzi, Mario Del Tacca
• Journal: Journal of medicinal chemistry (J Med Chem) Vol. 52 Issue 6 Pg. 1681-92 (Mar 26 2009) ISSN: 1520-4804 [Electronic] United States
• PMID: 19226143 (Publication Type: Journal Article)

Chemical References

• Adenosine Deaminase Inhibitors
• Enzyme Inhibitors
• Pyrazoles
• Pyridines
• pyrazolo(3,4-b)pyridine

Topics

• Adenosine Deaminase Inhibitors
• Animals
• Catalytic Domain
• Colitis (drug therapy)
• Dose-Response Relationship, Drug
• Enzyme Inhibitors (chemistry, pharmacology, therapeutic use)
• Pyrazoles (chemistry, pharmacology, therapeutic use)
• Pyridines (chemistry, pharmacology, therapeutic use)
• Rats
• Structure-Activity Relationship