New pyrazolo[3,4-b]pyridones as selective A(1) adenosine receptor antagonists: synthesis, biological evaluation and molecular modelling studies.
A series of ethyl 4-amino-1-(2-chloro-2-phenylethyl)-6-oxo-6,7-dihydro-1H-pyrazolo[3,4-b]pyridine-5-carboxylates () has been synthesized as potential A(1) adenosine receptor (A(1) AR) ligands. Binding affinities of the new compounds were determined for adenosine A(1), A(2A) and A(3) receptors. Compounds and showed good affinity (K(i)= 299 nM and 517 nM, respectively) and selectivity towards A(1) AR, whereas showed good affinity for A(2A) AR (K(i)= 290 nM), higher than towards A(1) AR (K(i)= 1000 nM). The only arylamino derivative of the series displayed high affinity (K(i)= 4.6 nM) and selectivity for A(3) AR. Molecular modelling and 3D-QSAR (CoMFA) studies carried out on the most active compounds gave further support to the pharmacological results.
Fossa
Paola
P
Dipartimento di Scienze Farmaceutiche, Università degli Studi di Genova, Viale Benedetto XV 3, 16132 Genova, Italy.
Pestarino
Marco
M
Menozzi
Giulia
G
Mosti
Luisa
L
Schenone
Silvia
S
Ranise
Angelo
A
Bondavalli
Francesco
F
Trincavelli
M Letizia
ML
Lucacchini
Antonio
A
Martini
Claudia
C
D008958:Models, Molecular; D058915:Purinergic P1 Receptor Antagonists; D011720:Pyrazoles / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D011725:Pyridines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D021281:Quantitative Structure-Activity Relationship
D058915:Purinergic P1 Receptor Antagonists; D011720:Pyrazoles; D011725:Pyridines; C447480:pyrazolo(3,4-b)pyridine