Synthesis and 3D QSAR of new pyrazolo[3,4-b]pyridines: potent and selective inhibitors of A1 adenosine receptors.
A number of 4-aminopyrazolo[3,4-b]pyridines 5-carboxylic acid esters (2-8) were synthesized and evaluated for their binding affinity at the A1, A2A, and A3 adenosine receptors (AR), in bovine cortical membranes, as well as for their affinity toward human A1AR (hA1AR). Some of the new compounds were characterized by a high affinity and selectivity toward the A1 receptor subtype, showing a significant improvement in comparison with other pyrazolo-pyridines previously reported in the literature. In particular the methyl ester 2h as well as the isopropyl ester 5h, both of them bearing a p-methoxyphenylethylamino side chain at the position 4, presented Ki values of 6 and 7 nM, respectively. To rationalize the relationships between structure and affinity of the novel compounds, a 3D QSAR model was also generated starting from compounds belonging to different classes of known A1AR antagonists.
Manetti
Fabrizio
F
Dipartimento Farmaco Chimico Tecnologico, Università degli Studi di Siena, Via Aldo Moro, I-53100 Siena, Italy.
Schenone
Silvia
S
Bondavalli
Francesco
F
Brullo
Chiara
C
Bruno
Olga
O
Ranise
Angelo
A
Mosti
Luisa
L
Menozzi
Giulia
G
Fossa
Paola
P
Trincavelli
Maria Letizia
ML
Martini
Claudia
C
Martinelli
Adriano
A
Tintori
Cristina
C
Botta
Maurizio
M
D058916:Adenosine A1 Receptor Antagonists; D000818:Animals; D002417:Cattle; D002540:Cerebral Cortex / Q000378:metabolism; D006801:Humans; D066298:In Vitro Techniques; D008958:Models, Molecular; D011720:Pyrazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D011725:Pyridines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D021281:Quantitative Structure-Activity Relationship; D011869:Radioligand Assay; D043682:Receptor, Adenosine A1 / Q000737:chemistry* / Q000378:metabolism; D043684:Receptor, Adenosine A3 / Q000378:metabolism; D043683:Receptors, Adenosine A2 / Q000378:metabolism
D058916:Adenosine A1 Receptor Antagonists; D011720:Pyrazoles; D011725:Pyridines; D043682:Receptor, Adenosine A1; D043684:Receptor, Adenosine A3; D043683:Receptors, Adenosine A2; C507024:isopropyl 1-(2-chloro-2-phenylethyl)-4-((2-(4-methoxyphenyl)ethyl)amino)-1H-pyrazolo(3,4-b)pyridine-5-carboxylate; C507023:methyl 1-(2-chloro-2-phenylethyl)-4-((2-(4-methoxyphenyl)ethyl)amino)-1H-pyrazolo(3,4-b)pyridine-5-carboxylate