jm050136d_si_001.pdf (37.16 kB)
Novel, Highly Potent Adenosine Deaminase Inhibitors Containing the Pyrazolo[3,4-d]pyrimidine Ring System. Synthesis, Structure−Activity Relationships, and Molecular Modeling Studies
journal contributionposted on 2005-08-11, 00:00 authored by Federico Da Settimo, Giampaolo Primofiore, Concettina La Motta, Sabrina Taliani, Francesca Simorini, Anna Maria Marini, Laura Mugnaini, Antonio Lavecchia, Ettore Novellino, Daniela Tuscano, Claudia Martini
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.