Discovery of 2-aminoimidazole and 2-amino imidazolyl-thiazoles as non-xanthine human adenosine A 3 receptor antagonists: SAR and molecular modeling studies.

A small-molecule combinatorial library of 24 compounds with 2-aminoimidazole and 2-aminoimidazolyl-thiazole derivatives was synthesized using a 2-chloro trityl resin. The generated compound library was tested against all the human adenosine receptors subtypes. The 2-aminoimidazole derivatives ( 6a-6l ) showed weak to moderate affinity towards the human adenosine receptors. Further modification to 2-aminoimidazolyl-thiazole derivatives ( 12a-12l ) resulted in an improvement of affinity at adenosine A ₁ , A _2A and A ₃ receptor subtypes. Compound 12b was the most potent and selective non-xanthine human adenosine A ₃ receptor antagonist of this series. A receptor-based modeling study was performed to explore the possible binding mode of these novel 2-aminoimidazole and 2-aminoimidazolyl-thiazole derivatives into human adenosine A ₁ , A _2A and A ₃ receptor subtypes.