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 A_2A Receptor Subtype

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 (R), was synthesized with the main purpose of targeting the hA adenosine receptor (AR). Several compounds possessed nanomolar affinity for the hA AR (K = 2.9-10 nM) and some, very interestingly, also showed high selectivity for the target. One selected potent hA AR antagonist (12, R = H, R = 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.

Catalytic Preparation of 1-Aryl-Substituted 1,2,4-Triazolium Salts

“…16−20 N -Aryl-substituted 1,2,4-triazoles are also frequent building blocks in organic compounds with biological activity. 21−23 Although less common than imidazolium or 1,2,3-triazolium salts, 1,2,4-triazolium salts have been successfully used as ionic liquids for dissolving cellulose. 24…”

Novel human adenosine receptor antagonists based on the 7-amino-thiazolo[5,4-d]pyrimidine scaffold. Structural investigations at the 2-, 5- and 7-positions to enhance affinity and tune selectivity

“…In continuation of our studies directed towards the identification of new AR antagonists [23][24][25][26][27][28], in a recent paper we disclosed the 5-methyl-2-phenylthiazolo [5,4-d]pyrimidin-7-one 1 [29] which proved to be a potent and selective human (h) A 3 AR antagonist, being inactive at the other AR subtypes (Fig. 1).…”

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

“…Indeed, four A2A AR antagonists, including Preladenant [17], PBF-509 [18], CPI-444 [19], and AZD4635 [20] have entered clinical development as anticancer drugs alone and in combination with other agents (Figure 1). Our group previously synthesized some potent human (h) A2A AR antagonists/inverse agonists belonging to different chemical classes [21][22][23][24][25][26][27][28][29][30][31]. Among these, the thiazolo [5,4-d]pyrimidine one (TP series) has been deeply investigated allowing us to delineate comprehensive structure activity relationships [21,[25][26][27]31].…”

“…Our group previously synthesized some potent human (h) A 2A AR antagonists/inverse agonists belonging to different chemical classes [ 21 , 22 , 23 , 24 , 25 , 26 , 27 , 28 , 29 , 30 , 31 ]. Among these, the thiazolo[5,4- d ]pyrimidine one (TP series) has been deeply investigated allowing us to delineate comprehensive structure activity relationships [ 21 , 25 , 26 , 27 , 31 ].…”