Novel, highly potent adenosine deaminase inhibitors containing the pyrazolo[3,4-d]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-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 K(i) 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 (K(i) 0.053 nM), showing an activity 2 orders of magnitude higher than that of (+)-EHNA (K(i) 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.
Da Settimo
Federico
F
Dipartimento di Scienze Farmaceutiche, Università di Pisa, Via Bonanno 6, 56126 Pisa, Italy.
Primofiore
Giampaolo
G
La Motta
Concettina
C
Taliani
Sabrina
S
Simorini
Francesca
F
Marini
Anna Maria
AM
Mugnaini
Laura
L
Lavecchia
Antonio
A
Novellino
Ettore
E
Tuscano
Daniela
D
Martini
Claudia
C
D058892:Adenosine Deaminase Inhibitors; D000818:Animals; D001665:Binding Sites; D001667:Binding, Competitive; D002417:Cattle; D002540:Cerebral Cortex / Q000378:metabolism; D018360:Crystallography, X-Ray; D066298:In Vitro Techniques; D008024:Ligands; D008958:Models, Molecular; D011720:Pyrazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D011743:Pyrimidines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D011869:Radioligand Assay; D013154:Spleen / Q000201:enzymology; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
C503894:2-(2-hydroxydecyl)-4-aminopyrazolo(3,4-d)pyrimidine; D058892:Adenosine Deaminase Inhibitors; D008024:Ligands; D011720:Pyrazoles; D011743:Pyrimidines