The 1,2,4-Triazolo[4,3-a]pyrazin-3-one as a Versatile Scaffold for the Design of Potent Adenosine Human Receptor Antagonists. Structural Investigations to Target the A2A Receptor Subtype

5 years ago

The 1,2,4-Triazolo[4,3-a]pyrazin-3-one as a Versatile Scaffold for the Design of Potent Adenosine Human Receptor Antagonists. Structural Investigations to Target the A2A Receptor Subtype

Lucia Squarcialupi, Matteo Falsini, Vittoria Colotta, Diego Dal Ben, Rosaria Volpini, Michela Buccioni, Daniela Catarzi, Gabriella Marucci, Teresa De Vita, Marco Betti, Flavia Varano, Andrea Cavalli

In this work, we describe the identification of the 1,2,4-triazolo[4,3-a]pyrazin-3-one as a new versatile scaffold for the development of adenosine human (h) receptor antagonists. The new chemotype ensued from a molecular simplification approach applied to our previously reported 1,2,4-triazolo[4,3-a]quinoxalin-1-one series. Hence, a set of novel 8-amino-2-aryl-1,2,4-triazolopyrazin-3-one derivatives, featured by different substituents on the 2-phenyl ring (R) and at position 6 (R₆), was synthesized with the main purpose of targeting the hA_2A adenosine receptor (AR). Several compounds possessed nanomolar affinity for the hA_2A AR (K_i = 2.9–10 nM) and some, very interestingly, also showed high selectivity for the target. One selected potent hA_2A AR antagonist (12, R = H, R₆ = 4-methoxyphenyl) demonstrated some ability to counteract MPP⁺-induced neurotoxicity in cultured human neuroblastoma SH-SY5Y cells, a widely used in vitro Parkinson’s disease model. Docking studies at hAR structures were performed to rationalize the observed affinity data.

Publisher URL: http://dx.doi.org/10.1021/acs.jmedchem.7b00457

DOI: 10.1021/acs.jmedchem.7b00457