Synthesis and study of 5′-ester prodrugs of N6-cyclopentgladenosine, a selective A1 receptor agonist

Purpose. A series of 5 ' -esters of N -cyclopentyladenosine (CPA) were prepared with the aim to improve stability and bioavailability of selective A(1) agonists. Log P values, stability, affinity, and activity toward human adenosine A, receptors were evaluated. Methods. An appropriate synthetic procedure was adopted to avoid concomitant deamination at position 6. Log P values were obtained by the Mixxor system. The stability of CPA and its 5 ' -ester was evaluated in human plasma and whole blood and analyzed with highperformance liquid chromatography. The affinities to human A, receptor expressed by N-6-cyclohexyladenosine cells were obtained by binding experiments. The activities were evaluated by measurements of the inhibition of forskolin stimulated 3 ' -5 ' -cyclic adenosine monophosphate, performing competitive binding assays. Results. All prodrugs were more lipophilic than CPA, and their hydrolysis, in whole blood and in plasma, was found related, respectively, to the length and hindrance of 5 ' -substituents. Affinity and activity values indicated a very weak interaction toward adenosine A, receptor of the intact prodrugs. Conclusions. We propose 5 ' -esters of CPA, characterized by suitable lipophilicity and elevated degree of stability in physiological fluids, as possible canditates for CPA prodrugs.