Pyrazolo[4,3-e][1,2,4]triazolo[1,5-c]pyrimidines and Structurally Simplified Analogs. Chemistry and SAR Profile as Adenosine Receptor Antagonists

Title:Pyrazolo[4,3-e][1,2,4]triazolo[1,5-c]pyrimidines and Structurally Simplified Analogs. Chemistry and SAR Profile as Adenosine Receptor Antagonists

Volume: 16 Issue: 28

Author(s): Sara Redenti, Antonella Ciancetta, Giorgia Pastorin, Barbara Cacciari, Stefano Moro, Giampiero Spalluto and Stephanie Federico

Affiliation:

Keywords: Pyrazolo[4, 3-e][1, 2, 4]triazolo[1, 5-c]pyrimidine, [1, 2, 4]triazolo[1, 5-c]pyrimidine, Pyrazolo[3, 4-d]pyrimidine, Adenosine receptors, Antagonists, Preladenant.

Abstract: Adenosine was defined as a neuromodulator which exerts its action by interaction with specific G-protein coupled receptor termed adenosine receptors. Adenosine receptors are expressed in several tissues and cells of our body and exist as four different subtypes of these receptors: A₁, A_2A, A_2B and A₃. In the last years significant efforts were made to obtain highly potent and selective ligands for the four adenosine receptors subtypes. Both agonists and antagonists were used as pharmacological tools to study therapeutic implications of enhancing or blocking the adenosine receptors activity, and some of these compounds have reached clinical phases. The pyrazolo[4,3-e][1,2,4]triazolo[1,5-c]pyrimidines (PTPs) represent one of the several templates designed as adenosine receptor antagonists. A lot of synthetic work was made on this scaffold in order to obtain potent A_2A and A₃ antagonists. Here were reviewed the synthetic approaches followed by both academia and industry to introduce different substituents at different positions of the PTP nucleus, in particular at the 2, 5, 7, 8 and 9 positions. Nevertheless PTP derivatives are tricyclic compounds with a high molecular weight which exhibit limitations such as poor aqueous solubility and difficult synthetic preparation. With the aim to obtain derivatives with the same potency and selectivity of PTP but with better drug-like properties, researchers made structural simplification of this scaffold. Replacement of the pyrazole or triazole rings of PTP led to the [1,2,4]triazolo[1,5-c]pyrimidine and pyrazolo[3,4- d]pyrimidine derivatives, respectively. Synthetic strategies for these compounds were reported, combined with the SAR profile on the adenosine receptors.

Cite this article as:

Redenti Sara, Ciancetta Antonella, Pastorin Giorgia, Cacciari Barbara, Moro Stefano, Spalluto Giampiero and Federico Stephanie, Pyrazolo[4,3-e][1,2,4]triazolo[1,5-c]pyrimidines and Structurally Simplified Analogs. Chemistry and SAR Profile as Adenosine Receptor Antagonists, Current Topics in Medicinal Chemistry 2016; 16 (28) . https://dx.doi.org/10.2174/1568026616666160506145831