37883-67-3Relevant academic research and scientific papers
Synthesis and evaluation of N-substituted 2-amino-4,5-diarylpyrimidines as selective adenosine A1receptor antagonists
Alachouzos, Georgios,Lenselink, Eelke B.,Mulder-Krieger, Thea,de Vries, Henk,IJzerman, Adriaan P.,Louvel, Julien
, p. 586 - 602 (2016/10/12)
We report the synthesis and biological evaluation of new 2-amino-4,5-diarylpyrimidines as selective antagonists at the adenosine A1receptor. 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 A2Asubtype. 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 (Ki(hA1AR) = 7.7 nM) and selective (Ki(hA2AAR) = 1389 nM) antagonist at the human adenosine A1receptor. Computational docking was effected at the A1and A2Asubtypes, 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.
