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 contribution
posted 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 MartiniThis 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.