Synthesis and structure–activity relationship of novel benzoxazole derivatives as melatonin receptor agonists

Atrial fibrillation (AF) is the most commonly encountered sustained clinical arrhythmia with an estimated 2.3 million cases in the US (2001). A1 adenosine receptor agonists can slow the electrical impulse propagation through the atrioventricular (AV) node (i.e., negative dromotropic effect) resulting in prolongation of the stimulus-to-His bundle (S-H) interval to potentially reduce ventricular rate. Compounds that are full agonists of the A1 adenosine receptor can cause high grade AV block. Therefore, it is envisioned that a compound that is a partial agonist of the A1 adenosine receptor could avoid this deleterious effect. 5′ Phenyl sulfides (e.g., 17, EC50=1.26 μM) and phenyl ethers (e.g., 28, EC50=0.2 μM) are partial agonists with respect to their AV nodal effects in guinea pig isolated hearts. Additional affinity, GTPγS binding data suggesting partial activity of the A1 adenosine receptor, and PK results for 5′ modified adenosine derivatives are shown.