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

Abstract

The amino-3,5-dicyanopyridine derivatives belong to an intriguing series of adenosine receptor (AR) ligands that has been developed by both academic researchers and industry. Indeed, the studies carried out to date underline the versatility of the dicyanopyridine scaffold to obtain AR ligands with not only a wide range of affinities but also with diverse degrees of efficacies at the different ARs. These observations prompted us to investigate on the structure–activity relationships (SARs) of this series leading to important previously reported results. The present SAR study has helped to confirm the 1H-imidazol-2-yl group at R2 position as an important feature for producing potent AR agonists. Moreover, the nature of the R1 substituent highly affects not only affinity/activity at the hA1 and hA2B ARs but also selectivity versus the other subtypes. Potent hA1 and hA2B AR ligands were developed, and among them, the 2-amino-6-[(1H-imidazol-2-ylmethyl)sulfanyl]-4-[4-(prop-2-en-1-yloxy)phenyl]pyridine-3,5-dicarbonitrile (3) is active in the low nanomolar range at these subtypes and shows a good trend of selectivity versus both the hA2A and hA3 ARs. This combined hA1/hA2B partial agonist activity leads to a synergistic effect on glucose homeostasis and could potentially be beneficial in treating diabetes and related complications.

Reactions of Malononitrile Dimer with Isothiocyanates

“…In silico assessment of biological activity. 6-Аminо-2-thioxopyridine-3,5-dicarbonitriles and their derivatives exhibit broad-spectrum biological activity (see reviews [38][39][40][41][42] and recent works [43][44][45][46][47][48]), which makes them promising objects for study. The biological activity of 2-аminоthiopyran-3,5-dicarbonitriles was also reported [49][50][51].…”

2-Amino-3,5-dicarbonitrile-6-sulfanylpyridines: synthesis and multiple biological activity – a review

“…Catarzi and co-workers developed a method for the synthesis of a series of new pyridines 50, which were studied for the structure–activity relationship with respect to adenosine receptors. 100 This approach is based on the transformation of the thiophenyl group in pyridines 4 into a mercapto group on treatment with Na 2 S followed by hydrolysis to thiol 48. The subsequent alkylation of 2-mercaptopyridine 48 with 2-(chloromethyl)-1 H -imidazole or methyl chloroacetate 52 in the presence of sodium hydrogen carbonate at room temperature afforded target pyridine 51 ( Scheme 13 ).…”

4-Heteroaryl Substituted Amino-3,5-Dicyanopyridines as New Adenosine Receptor Ligands: Novel Insights on Structure-Activity Relationships and Perspectives

“…The amino-3,5-dicyanopyridines have attracted much attention due to their versatility to behave as AR ligands. In fact, they are endowed with not only a wide range of affinity but also with different degrees of activities, with their profile varying from full to partial agonist or neutral antagonist at the different ARs [1][2][3][4][5][6][7]. As for other G-protein-coupled receptors [8][9][10], some of the antagonists have been proven to be inverse agonists [6].…”

“…Many publications report the amino-3,5-dicyanopyridines as AR ligands, showing nanomolar affinity and ranging from pan to selective AR ligands [1][2][3][4][5][6][7]. Moreover, this series seems to be more eclectic for pharmacological studies, because it is endowed with less species' differences with respect to the adenosine-like AR agonists [26].…”