The aminopyridine-3,5-dicarbonitrile core for the design of new non-nucleoside-like agonists of the human adenosine A2B receptor

Abstract

A new series of amino-3,5-dicyanopyridines (3-28) as analogues of the adenosine hA receptor agonist BAY60-6583 (compound 1) was synthesized. All the compounds that interact with the hA adenosine receptor display EC values in the range 9-350 nM behaving as partial agonists, with the only exception being the 2-{[4-(4-acetamidophenyl)-6-amino-3,5-dicyanopyridin-2-yl]thio}acetamide (8) which shows a full agonist profile. Moreover, the 2-[(1H-imidazol-2-yl)methylthio)]-6-amino-4-(4-cyclopropylmethoxy-phenyl)pyridine-3,5-dicarbonitrile (15) turns out to be 3-fold more active than 1 although less selective. This result can be considered a real breakthrough due to the currently limited number of non-adenosine hA AR agonists reported in literature. To simulate the binding mode of nucleoside and non-nucleoside agonists at the hA AR, molecular docking studies were performed at homology models of this AR subtype developed by using two crystal structures of agonist-bound A AR as templates. These investigations allowed us to represent a hypothetical binding mode of hA receptor agonists belonging to the amino-3,5-dicyanopyridine series and to rationalize the observed SAR.

Design, Sonosynthesis, Quantum‐Chemical Calculations, and Evaluation of New Mono‐ and Bis‐pyridine Dicarbonitriles as Antiproliferative Agents

“…Pyridines are among the most important biochemical scaffolds with broader uses in the medicinal and pharmaceutical industries as well as intermediates in heterocyclic preparations . Among pyridine derivatives, dicyanopyridines act as ‘privileged skeleton’ owing to their prospective uses for therapy . These derivatives were recorded to serve as anti‐prion, human adenosine A2B receptor, antibacterial, anti‐cancer, and anti‐hepatitis B virus .…”

Amino-3,5-Dicyanopyridines Targeting the Adenosine Receptors. Ranging from Pan Ligands to Combined A1/A2B Partial Agonists

“…Compounds 1-4, 6-20, and their corresponding intermediates were synthesized according to the procedure reported in Schemes 1-3. Following the same procedures, the 2-(((1H-Imidazol-2yl)methyl)thio)-6-amino-4-(4-ethoxyphenyl)pyridine-3,5-dicarbonitrile 5, previously reported in reference [12], was prepared. For the synthesis of derivatives 1-4, 6-13, and 20, the strategic intermediates are represented by the 6-sulfanyl-substituted compounds 28-40 [12,14,18,[20][21][22][23], which were prepared as depicted in Scheme 1.…”

“…The growing interest in this class is also dictated by the fact that non-nucleoside AR agonists seem to be more versatile for pharmacological studies, showing fewer species differences than the adenosine-like ones [4]. Moreover, the studies carried out to date are sufficient to underline the versatility of the amino-3,5-dicyanopyridine scaffold for producing AR ligands with not only a wide range of affinities but, interestingly, with different degrees of efficacy at the different ARs [11,12,[14][15][16][17][18][19].…”

“…Following the same procedures, the 2-(((1H-Imidazol-2-yl)methyl)thio)-6-amino-4-(4-ethoxyphenyl)pyridine-3,5-dicarbonitrile 5, previously reported in reference [12], was prepared. For the synthesis of derivatives 1-4, 6-13, and 20, the strategic intermediates are represented by the 6-sulfanyl-substituted compounds 28-40 [12,14,18,[20][21][22][23], which were prepared as depicted in Scheme 1. The suitable aldehyde was reacted with malononitrile and thiophenol, in boiling water, in the presence of a catalytic amount of basic alumina to yield the 4-aryl-and 4-benzyl-6-phenylsulfanyl-derivatives 21-27 [18,[24][25][26], with moderate to good yield.…”

“…BAY-606583 (2-{[6-Amino-3,5-dicyano-4-(4-(cyclopropylmethoxy)phenyl)pyridin-2-yl]thio}acetamide) is one of the most potent and selective A 2B AR agonists known to date [11]. However, we recently produced a new series of amino-3,5-dicyanopyridines as BAY-606583 analogues [12]; most of the compounds are potent human (h) A 2B AR partial agonists. Among them, the 2-{[(1H-imidazol-2-yl)methyl]thio}-6-amino-4-[4-(cyclopropylmethoxy)phenyl]pyridine-3,5-dicarbonitrile (P453, Figure 1) turns out to be three-fold more active than BAY-606583, although it is less selective.…”