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

Eur J Med Chem. 2020 Jan 15;186:111879. doi: 10.1016/j.ejmech.2019.111879. Epub 2019 Nov 15.


Adenosine acts as a powerful signaling molecule via four distinct G protein-coupled receptors, designated A1, A2A, A2B and A3 adenosine receptors (ARs). A2A and A2B ARs are Gs-coupled, while A1 and A3 ARs inhibit cAMP production via Gi proteins. Antagonists for A1 and A3 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 A1 and A3 AR antagonists including dual-target compounds. Selective A1 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 A1 AR, and were characterized as inverse agonists. Several potent and selective A3 AR antagonists, e.g. 7, 8, 17 and 22 (Ki values of 5-9 nM at the human A3 AR) were prepared, which were much less potent at the rat orthologue. Moreover, dual A1/A3 antagonists (10, 18) were developed showing Ki values between 8 and 42 nM. Docking and molecule dynamic simulation studies using the crystal structure of the A1 AR and a homology model of the A3 AR were performed to rationalize the observed structure-activity relationships.

Keywords: A(1) adenosine receptor; A(3) adenosine receptor antagonist; Adenosine receptors; Allosteric modulator; Alzheimer’s disease; Inverse agonist; Multi-target drugs; Selectivity; Species differences; Structure-activity relationships; Synthesis; Thiazole.

MeSH terms

  • Dose-Response Relationship, Drug
  • Humans
  • Models, Molecular
  • Molecular Structure
  • Purinergic P1 Receptor Antagonists / chemical synthesis
  • Purinergic P1 Receptor Antagonists / chemistry
  • Purinergic P1 Receptor Antagonists / pharmacology*
  • Receptor, Adenosine A1 / metabolism*
  • Receptor, Adenosine A3 / metabolism*
  • Structure-Activity Relationship
  • Thiazoles / chemical synthesis
  • Thiazoles / chemistry
  • Thiazoles / pharmacology*


  • Purinergic P1 Receptor Antagonists
  • Receptor, Adenosine A1
  • Receptor, Adenosine A3
  • Thiazoles