Substituted 4-phenylthiazoles: Development of potent and selective A, A and dual A/A adenosine receptor antagonists.

Adenosine acts as a powerful signaling molecule via four distinct G protein-coupled receptors, designated A, A, A and A adenosine receptors (ARs). A and A ARs are G-coupled, while A and A ARs inhibit cAMP production via G proteins. Antagonists for A and A ARs may be useful for the treatment of (neuro)inflammatory diseases including acute kidney injury and kidney failure, pulmonary diseases, and Alzheimer's disease. In the present study, we optimized the versatile 2-amino-4-phenylthiazole scaffold by introducing substituents at N2 and C5 to obtain A and A AR antagonists including dual-target compounds. Selective A antagonists with (sub)nanomolar potency were produced, e.g. 11 and 13. These compounds showed species differences being significantly more potent at the rat as compared to the human A AR, and were characterized as inverse agonists. Several potent and selective A AR antagonists, e.g. 7, 8, 17 and 22 (K values of 5-9 nM at the human A AR) were prepared, which were much less potent at the rat orthologue. Moreover, dual A/A antagonists (10, 18) were developed showing K values between 8 and 42 nM. Docking and molecule dynamic simulation studies using the crystal structure of the A AR and a homology model of the A AR were performed to rationalize the observed structure-activity relationships.