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

Abstract

This paper describes the synthesis of novel 7-amino-thiazolo [5,4-d]pyrimidines bearing different substituents at positions 2 , 5 and 7 of the thiazolopyrimidine scaffold. The synthesized compounds 2-27 were evaluated in radioligand binding (A 1 , A 2A and A 3 ) and adenylyl cyclase activity (A 2B and A 2A ) assays, in order to evaluate their affinity and potency at human adenosine receptor subtypes.The current study allowed us to support that affinity and selectivity of 7-amino-thiazolo [5,4d]pyrimidine derivatives towards the adenosine receptor subtypes can be modulated by the nature of the groups attached at positions 2, 5 and 7 of the bicyclic scaffold. To rationalize the hypothetical binding mode of the newly synthesized compounds, we also performed docking calculations in human A 2A , A 1 and A 3 structures.

Design and Synthesis of Novel Thiazolo[5,4-d]pyrimidine Derivatives with High Affinity for Both the Adenosine A1 and A2A Receptors, and Efficacy in Animal Models of Depression

“…[ 26 , 27 , 28 , 29 , 30 ]. Within this research, an interesting class of antagonists/inverse agonists (i.e., the thiazolo[5,4-d]pyrimidine series) was identified [ 31 , 32 , 33 , 34 , 35 ]. Recently, we investigated the 7-amino-thiazolo[5,4-d]pyrimidine series A ( Figure 1 ) featured by a phenyl or a furan-2yl ring at position 2 (R 2 ) combined with an aryl or heteroaryl group at position 5 (R 5 ) [ 34 ].…”

“…Based on these findings, we herein report on the design and synthesis of new 7-aminothiazolopyrimidines 1 – 19 to obtain more potent A 1 and/or A 2A AR antagonists. To this goal, compounds 1 – 19 were decorated at position-5 with selected substituents that in previously reported compounds of series A enhanced affinity toward A 1 and/or A 2A AR (i.e., an unsubstituted or 3-CN or 3-OH substituted phenyl ring, and a heteroaryl moiety (furan-2yl or 5-methyl-furan-2yl) [ 34 ]), while at position-2, a benzyl or an ortho-substituted benzyl moiety was introduced since it improved A 2A AR affinity in other classes of our bicyclic dual A 1 /A 2A antagonists [ 26 ].…”

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 ]. This was possible because the central thiazolopyrimidine scaffold can be easily decorated by at least three different substituents at positions 2, 5, and 7, to explore diverse sites of interaction.…”

“…In contrast, substituents endowed with variable properties, such as the steric hindrance, seems to be tolerated at position 5. In fact, good to high A 2A AR affinity was observed when an (hetero)aryl or alkyl residue was attached by diverse linkers at position 5 of the thiazolopyrimidine scaffold [ 21 , 25 , 26 , 27 ]. In particular, in a recent paper by us some interesting results were obtained when the linker was a piperazine moiety directly attached to the bicyclic core or spaced by an ethylamino chain [ 31 ].…”