Design, Synthesis, and Pharmacological Characterization of 2-(2-Furanyl)thiazolo[5,4-d]pyrimidine-5,7-diamine Derivatives: New Highly Potent A_2A Adenosine Receptor Inverse Agonists with Antinociceptive Activity

Abstract

In this study, we describe the design and synthesis of new N-substituted-2-(2-furanyl) thiazolo[5,4-d]pyrimidine-5,7-diamines (2-18) and their pharmacological characterization as A adenosine receptor (AR) antagonists by using in vitro and in vivo assays. In competition binding experiments two derivatives (13 and 14) emerged as outstanding ligands showing two different affinity values (KH and KL) for the hA receptor with the high affinity KH value in the femtomolar range. The in vitro functional activity assays, performed by using cyclic AMP experiments, assessed that they behave as potent inverse agonists at the hA AR. Compounds 13 and 14 were evaluated for their antinociceptive activity in acute experimental models of pain showing an effect equal to or greater than that of morphine. Overall, these novel inverse agonists might represent potential drug candidates for an alternative approach to the management of pain.

Inhibition of A2A Adenosine Receptor Signaling in Cancer Cells Proliferation by the Novel Antagonist TP455

“…The A 2A AR antagonist/inverse agonist TP455 was recently synthesized (compound 13 in Varano et al, 2016 ) and the chemical structure is shown in Figure 1 . [ 3 H]-ZM 241385 was from PerkinElmer (Milan, Italy).…”

“…Recently, a series of novel blockers, having the thiazolo[5,4-d]pyrimidine nucleus, showing an unprecedented high affinity for the A 2A AR and a behavior as antagonists and/or inverse agonists has been developed ( Varano et al, 2016 ). With the availability of the novel compound 2-(2-furanyl)-N 5 -(2-methoxybenzyl)[1,3]thiazolo[5,4-d]pyrimidine-5,7-diammine (TP455) ( Figure 1 ), the involvement of A 2A ARs in human A375 melanoma, as well as in human A549 lung and rat MRMT1 breast carcinoma proliferation was evaluated.…”

Crystal structure and Hirshfeld surface analysis of 3,6-bis(pyrimidin-2-yl)-1,4-dihydro-1,2,4,5-tetrazine dihydrate

“…The chemistry of nitrogen-containing heterocyclic compounds has attracted the attention of the scientific community for over a century. Many compounds of this class are bioactive (Jubeen et al, 2018) and show promising pharmacological properties (Alcaide et al, 2016;Varano et al, 2016). Among these, numerous pyrimidine derivatives have been studied extensively in the context of synthetic organic chemistry and coordination chemistry (Kaim, 2002).…”

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].…”