Synthesis and biological evaluation of novel N-6-[4-(substituted) sulfonamidophenylcarbamoyl]adenosine-5 '-uronamides as A(3) adenosine receptor agonists

A new series of 1-deoxy-1-[(6-(4-(substituted-aminosulfonyl)phenyl)amino)carbonylamino-9H-purin-9-yl]-N-ethyl--D-ribofuranuronamides I (R, R1 = cyclic or linear aliph. group or arom. radicals) have been synthesized and tested at the human A3 adenosine receptor subtype. All the derivs. described in this work displayed affinity vs. this receptor in the nanomolar range and good selectivity vs. A1 adenosine receptor subtype, confirming that the p-sulfonamido moiety pos. affected the activity of the mols. The best substituents at the sulfonamido nucleus were found to be small alkyl groups, like Me, iso-Pr, Et, or allyl moieties, whereas mono-substitution at the amino group led to a decrease in A3 affinity values. The selectivity vs. A1 adenosine receptor subtype is increased when the amino group in the sulfonamido core is represented by a hydrogenated heterocyclic ring like piperidine, morpholine, or pyrroline. Bulky groups, like adamantane and alkyl chains with more than four carbon atoms, are detrimental for the affinity and the selectivity of the A3 adenosine receptor agonists described here.