%0 Journal Article %A Settimo, Federico Da %A Primofiore, Giampaolo %A Motta, Concettina La %A Taliani, Sabrina %A Simorini, Francesca %A Marini, Anna Maria %A Mugnaini, Laura %A Lavecchia, Antonio %A Novellino, Ettore %A Tuscano, Daniela %A Martini, Claudia %D 2005 %T Novel, Highly Potent Adenosine Deaminase Inhibitors Containing the Pyrazolo[3,4-d]pyrimidine Ring System. Synthesis, Structure−Activity Relationships, and Molecular Modeling Studies %U https://acs.figshare.com/articles/journal_contribution/Novel_Highly_Potent_Adenosine_Deaminase_Inhibitors_Containing_the_Pyrazolo_3_4_i_d_i_pyrimidine_Ring_System_Synthesis_Structure_Activity_Relationships_and_Molecular_Modeling_Studies/3273286 %R 10.1021/jm050136d.s001 %2 https://acs.figshare.com/ndownloader/files/5111005 %K study reports %K APP %K series %K ADA binding site %K alkyl chain %K activity 2 orders %K Docking simulations %K K i values %K decyl chain %K pyrimidine Ring System %K aminopyrazolopyrimidine %K Potent Adenosine Deaminase Inhibitors Containing %K 3 k %K inhibitor %K nM %K EHNA %K Molecular Modeling Studies %K decyl substituent %X 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 n-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. %I ACS Publications