Identification of novel thiazolo[5,4-d]pyrimidine derivatives as human A1 and A2A adenosine receptor antagonists/inverse agonists

Abstract

In this study a new set of thiazolo[5,4-d]pyrimidine derivatives was synthesized. These derivatives bear different substituents at positions 2 and 5 of the thiazolopyrimidine core while maintaining a free amino group at position-7. The new compounds were tested for their affinity and potency at human (h) A₁, A_2A, A_2B and A₃ adenosine receptors expressed in CHO cells. The results reveal that the higher affinity of these new set of thiazolopyrimidines is toward the hA₁ and hA_2A adenosine receptors subtypes and is tuned by the substitution pattern at both the 2 and 5 positions of the thiazolopyrimidine nucleus. Functional studies evidenced that the compounds behaved as dual A₁/A_2A antagonists/inverse agonists. Compound 3, bearing a 5-((2-methoxyphenyl) methylamino) group and a phenyl moiety at position 2, displayed the highest affinity (hA₁ K_i = 10.2 nM; hA_2A K_i = 4.72 nM) and behaved as a potent A₁/A_2A antagonist/inverse agonist (hA₁ IC₅₀ = 13.4 nM; hA_2A IC₅₀ = 5.34 nM).

Keywords: A(2A) adenosine receptors; Bicyclic heteroaromatic system; G protein-coupled receptors; Inverse agonists; Thiazolopyrimidine derivatives.