Synthesis and evaluation of N-substituted 2-amino-4,5-diarylpyrimidines as selective adenosine A1 receptor antagonists

Abstract

We report the synthesis and biological evaluation of new 2-amino-4,5-diarylpyrimidines as selective antagonists at the adenosine A₁ receptor. The scaffold they are based upon is a deaza variation of a previously reported collection of 3-amino-5,6-diaryl-1,2,4-triazines, members of which had a subnanomolar affinity but limited selectivity over the A_2A subtype. Initially, similar structure-affinity relationships at the 5-aryl ring were established, and then emphasis was put on increasing selectivity at the hA₁AR by introducing substituents on the N²-position, all the while maintaining a nanomolar affinity. Compound 3z, bearing a trans 4-hydroxycyclohexyl substituent, was identified as a potent (K_i(hA₁AR) = 7.7 nM) and selective (K_i(hA_2AAR) = 1389 nM) antagonist at the human adenosine A₁ receptor. Computational docking was effected at the A₁ and A_2A subtypes, rationalizing the effect of the 4-hydroxycyclohexyl substituent on selectivity, in relation with the nature of the substituent on the 5-position of the pyrimidine.

Keywords: Adenosine A(1) receptor; Adenosine A(2A) receptor; Antagonists; Selectivity; Structure-affinity relationships.