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 hA2A adenosine receptor (AR). Several compounds possessed nanomolar affinity for the hA2A AR (Ki = 2.9−10 nM) and some, very interestingly, also showed high selectivity for the target. One selected potent hA2A 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.

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 / Falsini, Matteo; Squarcialupi, Lucia; Catarzi, Daniela; Varano, Flavia; Betti, Marco; Dal Ben, Diego; Marucci, Gabriella; Buccioni, Michela; Volpini, Rosaria; De Vita, Teresa; Cavalli, Andrea; Colotta, Vittoria. - In: JOURNAL OF MEDICINAL CHEMISTRY. - ISSN 0022-2623. - STAMPA. - 60(2017), pp. 5772-5790. [10.1021/acs.jmedchem.7b00457]

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

FALSINI, MATTEO;SQUARCIALUPI, LUCIA;CATARZI, DANIELA;VARANO, FLAVIA;BETTI, MARCO;COLOTTA, VITTORIA
2017

Abstract

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 hA2A adenosine receptor (AR). Several compounds possessed nanomolar affinity for the hA2A AR (Ki = 2.9−10 nM) and some, very interestingly, also showed high selectivity for the target. One selected potent hA2A 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.
60
5772
5790
Falsini, Matteo; Squarcialupi, Lucia; Catarzi, Daniela; Varano, Flavia; Betti, Marco; Dal Ben, Diego; Marucci, Gabriella; Buccioni, Michela; Volpini, Rosaria; De Vita, Teresa; Cavalli, Andrea; Colotta, Vittoria
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Utilizza questo identificativo per citare o creare un link a questo documento: http://hdl.handle.net/2158/1093308
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