Capadenoson, a Clinically Trialed Partial Adenosine A Receptor Agonist, Can Stimulate Adenosine A Receptor Biased Agonism

The adenosine A receptor (AAR) has been identified as an important therapeutic target in cardiovascular disease, however in vitro and in vivo targeting has been limited by the paucity of pharmacological tools, particularly potent agonists. Interestingly, 2-((6-amino-3,5-dicyano-4-(4-(cyclopropylmethoxy)phenyl)-2-pyridinyl)thio)acetamide (BAY60-6583), a potent and subtype-selective AAR agonist, has the same core structure as 2-amino-6-[[2-(4-chlorophenyl)-1,3-thiazol-4-yl]methylsulfanyl]-4-[4-(2-hydroxyethoxy)phenyl]pyridine-3,5-dicarbonitril (capadenoson). Capadenoson, currently classified as an adenosine A receptor (AAR) partial agonist, has undergone two Phase IIa clinical trials, initially in patients with atrial fibrillation and subsequently in patients with stable angina. Capadenoson has also been shown to decrease cardiac remodeling in an animal model of advanced heart failure and a capadenoson derivative, neladenoson bialanate, recently entered clinical development for the treatment of chronic heart failure. The therapeutic effects of capadenoson are currently thought to be mediated through the AAR. However, the ability of capadenoson to stimulate additional adenosine receptor subtypes, in particular the AAR, has not been rigorously assessed. In this study, we demonstrate that capadenoson does indeed have significant AAR activity in physiologically relevant cells, cardiac fibroblasts and cardiomyocytes, which endogenously express the AAR. Relative to the non-selective adenosine receptor agonist NECA, capadenoson was a biased AAR agonist with a preference for cAMP signal transduction over other downstream mediators in cells with recombinant and endogenous AAR expression. These findings suggest the reclassification of capadenoson as a dual AAR/AAR agonist. Furthermore, a potential AAR contribution should be an important consideration for the future clinical development of capadenoson-like therapeutics, as the AAR can promote cardioprotection and modulate cardiac fibrosis in heart disease.