Modifications on the amino-3,5-dicyanopyridine core to obtain multifaceted adenosine receptor ligands with antineuropathic activity.

doi:10.1021/acs.jmedchem.9b00106

Paper

Modifications on the amino-3,5-dicyanopyridine core to obtain multifaceted adenosine receptor ligands with antineuropathic activity.

Published Jul 15, 2019 · M. Betti, D. Catarzi, F. Varano

Journal of medicinal chemistry

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15

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Abstract

A new series of amino-3,5-dicyanopyridines (1-31) was synthesized and biologically evaluated in order to further investigate the potential of this scaffold to obtain adenosine receptor (AR) ligands. In general, the modifications performed have led to compounds having from high to good human (h) A1AR affinity and an inverse agonist profile. While most of the compounds are hA1AR selective, some derivatives behave as mixed hA1AR inverse agonists/A2A and A2B AR antagonists. These latter (compound 9-12) showed to reduce oxaliplatin-induced neuropathic pain by a mechanism involving the alpha7 subtype of nAchRs, similarly to the non-selective AR antagonist caffeine, taken as reference compound. Along with the pharmacological evaluation, chemical stability of the methyl 3-(((6-amino-3,5-dicyano-4-(furan-2-yl)pyridin-2-yl)sulfanyl)methyl)benzoate 10 was assessed in plasma matrices (rat and human), and molecular modeling studies were carried out to better rationalize the available SARs.

In Vitro Study

Study Snapshot

The new series of amino-3,5-dicyanopyridines shows potential as adenosine receptor ligands with antineuropathic activity, with some showing mixed hA1AR inverse agonist/A2A and A2B antagonist activity.

PopulationOlder adults (50-71 years)

Sample size24

MethodsObservational

OutcomesBody Mass Index projections

ResultsSocial networks mitigate obesity in older groups.

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Paper

Modifications on the amino-3,5-dicyanopyridine core to obtain multifaceted adenosine receptor ligands with antineuropathic activity.

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Citations

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Novel thiazolo[5,4-d]pyrimidine derivatives show high affinity for both adenosine A1 and A2A receptors, with potential antidepressant-like activity in animal models.

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