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 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. The latter compounds (9-12) showed that they reduce oxaliplatin-induced neuropathic pain by a mechanism involving the alpha7 subtype of nAchRs, similar to the nonselective AR antagonist caffeine, taken as the reference compound. Along with the pharmacological evaluation, chemical stability of 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 structure-activity relationships.

Modifications on the Amino-3,5-dicyanopyridine Core To Obtain Multifaceted Adenosine Receptor Ligands with Antineuropathic Activity / Betti, Marco; Catarzi, Daniela; Varano, Flavia; Falsini, Matteo; Varani, Katia; Vincenzi, Fabrizio; Pasquini, Silvia; di Cesare Mannelli, Lorenzo; Ghelardini, Carla; Lucarini, Elena; Dal Ben, Diego; Spinaci, Andrea; Bartolucci, Gian Luca; Menicatti, Marta; Colotta, Vittoria. - In: JOURNAL OF MEDICINAL CHEMISTRY. - ISSN 0022-2623. - STAMPA. - 62:(2019), pp. 6894-6912. [10.1021/acs.jmedchem.9b00106]

Modifications on the Amino-3,5-dicyanopyridine Core To Obtain Multifaceted Adenosine Receptor Ligands with Antineuropathic Activity

Catarzi, Daniela
;
Varano, Flavia;Falsini, Matteo;di Cesare Mannelli, Lorenzo;Ghelardini, Carla;Lucarini, Elena;Bartolucci, Gian Luca;Menicatti, Marta;Colotta, Vittoria
2019

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 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. The latter compounds (9-12) showed that they reduce oxaliplatin-induced neuropathic pain by a mechanism involving the alpha7 subtype of nAchRs, similar to the nonselective AR antagonist caffeine, taken as the reference compound. Along with the pharmacological evaluation, chemical stability of 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 structure-activity relationships.
2019
62
6894
6912
Goal 3: Good health and well-being
Betti, Marco; Catarzi, Daniela; Varano, Flavia; Falsini, Matteo; Varani, Katia; Vincenzi, Fabrizio; Pasquini, Silvia; di Cesare Mannelli, Lorenzo; Ghe...espandi
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Utilizza questo identificatore per citare o creare un link a questa risorsa: https://hdl.handle.net/2158/1170035
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