PURPOSE: A series of 5'-esters of N6-cyclopentyladenosine (CPA) were prepared with the aim to improve stability and bioavailability of selective A1 agonists. Log P values, stability, affinity, and activity toward human adenosine A1 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 high-performance liquid chromatography. The affinities to human A1 receptor expressed by N6-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 A1 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 candidates for CPA prodrugs.
PURPOSE: A series of 5'-esters of N6-cyclopentyladenosine (CPA) were prepared with the aim to improve stability and bioavailability of selective A1 agonists. Log P values, stability, affinity, and activity toward human adenosine A1 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 high-performance liquid chromatography. The affinities to human A1 receptor expressed by N6-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 A1 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 candidates for CPA prodrugs.
Authors: R A Mathôt; E A van Schaick; M W Langemeijer; W Soudijn; D D Breimer; A P Ijzerman; M Danhof Journal: J Pharmacol Exp Ther Date: 1994-02 Impact factor: 4.030
Authors: Joseph E Rittiner; Ilia Korboukh; Emily A Hull-Ryde; Jian Jin; William P Janzen; Stephen V Frye; Mark J Zylka Journal: J Biol Chem Date: 2012-01-03 Impact factor: 5.157