2-Pyrazolyl-N(6)-substituted adenosine derivatives as high affinity and selective adenosine A(3) receptor agonists.

We describe the synthesis of new high affinity and selective A(3)-adenosine receptor (A(3)-AdoR) agonists. Introduction of a methyl group at the N(6)-position of the A(2A)-AdoR selective 2-pyrazolyl-adenosine analogues (Figure 2) brought about a substantial increase in the A(3)-AdoR binding affinity and selectivity. While the N(6)-desmethyl analogues 3a and 4 were inactive at the A(3)-AdoR (K(i) > 10 microM), the corresponding N(6)-methyl analogues 5 and 22 showed good binding affinity at the A(3)-AdoR (K(i) = 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 A(3)-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, K(i) = 2 nM) displayed high selectivity for the A(3)-AdoR versus A(1)- and A(2A)-AdoRs (selectivity ratios of 1900 and >2000, respectively).