Substituted 4-phenylthiazoles: Development of potent and selective A1, A3 and dual A1/A3 adenosine receptor antagonists

Adenosine acts as a powerful signaling molecule via four distinct G protein-coupled receptors, designated A(1), A(2A), A(2B) and A(3) adenosine receptors (ARs). A(2A) and A(2B) ARs are G(s)-coupled, while A(1) and A(3) ARs inhibit cAMP production via G, proteins. Antagonists for A(1) and A(3) 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 t and A3 AR antagonists including dual-target compounds. Selective A(1) 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(1) AR, and were characterized as inverse agonists. Several potent and selective A(3) AR antagonists, e.g. 7, 8, 17 and 22 (K-i values of 5-9 nM at the human A(3) AR) were prepared, which were much less potent at the rat orthologue. Moreover, dual A(1)/A(3) antagonists (10, 18) were developed showing K-i values between 8 and 42 nM. Docking and molecule dynamic simulation studies using the crystal structure of the A(1) AR and a homology model of the A(3) AR were performed to rationalize the observed structure-activity relationships. (C) 2019 Elsevier Masson SAS. All rights reserved.