Piperazine- and Piperidine-Containing Thiazolo[5,4-<i>d</i>]pyrimidine Derivatives as New Potent and Selective Adenosine A_2A Receptor Inverse Agonists

• Main Authors: Flavia Varano (Author), Daniela Catarzi (Author), Erica Vigiani (Author), Fabrizio Vincenzi (Author), Silvia Pasquini (Author), Katia Varani (Author), Vittoria Colotta (Author)
• Format: Book
• Published: MDPI AG, 2020-07-01T00:00:00Z.
• Subjects: article
• Online Access: Connect to this object online.
• Notes: 10.3390/ph13080161; 1424-8247
• Keywords: G protein-coupled receptors; adenosine receptors; adenosine A_2A receptor ligands; thiazolo[5,4-<i>d</i>]pyrimidines; Medicine; R; Pharmacy and materia medica; RS1-441
• Source: Pharmaceuticals, Vol 13, Iss 8, p 161 (2020)

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-<i>d</i>]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)-<i>N</i>⁵-(2-(4-phenylpiperazin-1-yl)ethyl)thiazolo[5,4-<i>d</i>]pyrimidine-5,7-diamine <b>11</b> 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 <b>8</b>, <b>11</b>, and <b>19</b> possessed good drug-likeness profiles.