2-Pyrazolyl-N6-Substituted Adenosine Derivatives as High Affinity and Selective Adenosine A3Receptor Agonists

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Abstract
We describe the synthesis of new high affinity and selective A3-adenosine receptor (A3-AdoR) agonists. Introduction of a methyl group at the N6-position of the A2A-AdoR selective 2-pyrazolyl-adenosine analogues (Figure 2) brought about a substantial increase in the A3-AdoR binding affinity and selectivity. While the N6-desmethyl analogues 3a and 4 were inactive at the A3-AdoR (Ki > 10 μM), the corresponding N6-methyl analogues 5 and 22 showed good binding affinity at the A3-AdoR (Ki = 73 and 97 nM, respectively). Replacement of the carboxamide group in 5 with different heteroaryl groups resulted in analogues with high affinities and selectivity for the A3-AdoR. (2R,3S,4R)-tetrahydro-2-(hydroxymethyl)-5-(6-(methylamino)-2-(4-(pyridin-2-yl)-1H-pyrazol-1-yl)-9H-purin-9-yl)furan-3,4-diol (15, Ki = 2 nM) displayed high selectivity for the A3-AdoR versus A1- and A2A-AdoRs (selectivity ratios of 1900 and >2000, respectively).