Synthesis and 3D QSAR of New Pyrazolo[3,4-b]pyridines:  Potent and Selective Inhibitors of A1 Adenosine Receptors

• Published in: Journal of medicinal chemistry Vol. 48; no. 23; pp. 7172 - 7185
• Main Authors: Manetti, Fabrizio, Schenone, Silvia, Bondavalli, Francesco, Brullo, Chiara, Bruno, Olga, Ranise, Angelo, Mosti, Luisa, Menozzi, Giulia, Fossa, Paola, Trincavelli, Maria Letizia, Martini, Claudia, Martinelli, Adriano, Tintori, Cristina, Botta, Maurizio
• Format: Journal Article
• Language: English
• Published: Washington, DC American Chemical Society 17.11.2005
• Subjects: Adenosine A1 Receptor Antagonists; Animals; Biological and medical sciences; Cattle; Cerebral Cortex - metabolism; Humans; In Vitro Techniques; Medical sciences; Models, Molecular; Neuropharmacology; Neurotransmitters. Neurotransmission. Receptors; Peptidergic system (neuropeptide, opioid peptide, opiates...). Adenosinergic and purinergic systems; Pharmacology. Drug treatments; Pyrazoles - chemical synthesis; Pyrazoles - chemistry; Pyrazoles - pharmacology; Pyridines - chemical synthesis; Pyridines - chemistry; Pyridines - pharmacology; Quantitative Structure-Activity Relationship; Radioligand Assay; Receptor, Adenosine A1 - chemistry; Receptor, Adenosine A1 - metabolism; Receptor, Adenosine A3 - metabolism; Receptors, Adenosine A2 - metabolism; Three dimensional model; Structure activity relation; Molecular model; Prediction; A1 Adenosine receptor; Inhibitor; Selectivity; Chemical synthesis; Modeling
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm050407k

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 K i 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.