Settimo, Federico Da Primofiore, Giampaolo Motta, Concettina La Taliani, Sabrina Simorini, Francesca Marini, Anna Maria Mugnaini, Laura Lavecchia, Antonio Novellino, Ettore Tuscano, Daniela Martini, Claudia 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 This study reports the synthesis of a number of 1- and 2-alkyl derivatives of the 4-aminopyrazolo[3,4-<i>d</i>]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 <i>K</i><sub>i</sub> 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 <i>n</i>-decyl substituent. Insertion of a 2‘-hydroxy group in the <i>n</i>-decyl chain gave <b>3k</b>, whose (<i>R</i>)-isomer displayed the highest inhibitory potency of the series (<i>K</i><sub>i</sub> 0.053 nM), showing an activity 2 orders of magnitude higher than that of (+)-EHNA (<i>K</i><sub>i</sub> 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. study reports;APP;series;ADA binding site;alkyl chain;activity 2 orders;Docking simulations;K i values;decyl chain;pyrimidine Ring System;aminopyrazolopyrimidine;Potent Adenosine Deaminase Inhibitors Containing;3 k;inhibitor;nM;EHNA;Molecular Modeling Studies;decyl substituent 2005-08-11
    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
10.1021/jm050136d.s001