Abstract
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.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Adenosine A1 Receptor Antagonists*
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Animals
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Cattle
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Cerebral Cortex / metabolism
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Humans
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In Vitro Techniques
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Models, Molecular
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Pyrazoles / chemical synthesis*
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Pyrazoles / chemistry
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Pyrazoles / pharmacology
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Pyridines / chemical synthesis*
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Pyridines / chemistry
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Pyridines / pharmacology
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Quantitative Structure-Activity Relationship*
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Radioligand Assay
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Receptor, Adenosine A1 / chemistry*
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Receptor, Adenosine A1 / metabolism
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Receptor, Adenosine A3 / metabolism
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Receptors, Adenosine A2 / metabolism
Substances
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Adenosine A1 Receptor Antagonists
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Pyrazoles
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Pyridines
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Receptor, Adenosine A1
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Receptor, Adenosine A3
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Receptors, Adenosine A2
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isopropyl 1-(2-chloro-2-phenylethyl)-4-((2-(4-methoxyphenyl)ethyl)amino)-1H-pyrazolo(3,4-b)pyridine-5-carboxylate
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methyl 1-(2-chloro-2-phenylethyl)-4-((2-(4-methoxyphenyl)ethyl)amino)-1H-pyrazolo(3,4-b)pyridine-5-carboxylate