Piperazine- and Piperidine-Containing Thiazolo[5,4- d]pyrimidine Derivatives as New Potent and Selective Adenosine A2A Receptor Inverse Agonists

Abstract

The therapeutic use of A_2A adenosine receptor (AR) antagonists for the treatment of neurodegenerative disorders, such as Parkinson and Alzheimer diseases, is a very promising approach. Moreover, the potential therapeutic role of A_2A AR antagonists to avoid both immunoescaping of tumor cells and tumor development is well documented. Herein, we report on the synthesis and biological evaluation of a new set of piperazine- and piperidine- containing 7-amino-2-(furan-2-yl)thiazolo[5,4-d]pyrimidine derivatives designed as human A_2A AR antagonists/inverse agonists. Binding and potency data indicated that a good number of potent and selective hA_2A AR inverse agonists were found. Amongst them, the 2-(furan-2-yl)-N⁵-(2-(4-phenylpiperazin-1-yl)ethyl)thiazolo[5,4-d]pyrimidine-5,7-diamine 11 exhibited the highest A_2A AR binding affinity (K_i = 8.62 nM) as well as inverse agonist potency (IC₅₀ = 7.42 nM). In addition, bioinformatics prediction using the web tool SwissADME revealed that 8, 11, and 19 possessed good drug-likeness profiles.

Keywords: G protein-coupled receptors; adenosine A2A receptor ligands; adenosine receptors; thiazolo[5,4-d]pyrimidines.