The role of 5-arylalkylamino- and 5-piperazino- moieties on the 7-aminopyrazolo[4,3-d]pyrimidine core in affecting adenosine A₁ and A_2A receptor affinity and selectivity profiles

Abstract

New 7-amino-2-phenylpyrazolo[4,3-d]pyrimidine derivatives, substituted at the 5-position with aryl(alkyl)amino- and 4-substituted-piperazin-1-yl- moieties, were synthesized with the aim of targeting human (h) adenosine A1 and/or A2A receptor subtypes. On the whole, the novel derivatives 1–24 shared scarce or no affinities for the off-target hA2B and hA3 ARs. The 5-(4-hydroxyphenethylamino)- derivative 12 showed both good affinity (Ki = 150 nM) and the best selectivity for the hA2A AR while the 5-benzylamino-substituted 5 displayed the best combined hA2A (Ki = 123 nM) and A1 AR affinity (Ki = 25 nM). The 5-phenethylamino moiety (compound 6) achieved nanomolar affinity (Ki = 11 nM) and good selectivity for the hA1 AR. The 5-(N4-substituted-piperazin-1-yl) derivatives 15–24 bind the hA1 AR subtype with affinities falling in the high nanomolar range. A structure-based molecular modeling study was conducted to rationalize the experimental binding data from a molecular point of view using both molecular docking studies and Interaction Energy Fingerprints (IEFs) analysis.

Development of Adenosine A2A Receptor Antagonists for the Treatment of Parkinson’s Disease: A Recent Update and Challenge

“…Compound 19 was identified as a potent A 2A antagonist (A 2A K i = 2.2 nM) with much improved metabolic stability . In HLM, ST1535 ( 3 ) was rapidly degraded with a half-life of 13.7 min while 19 remained almost unchanged after 2 h. In an effort to comprehensively profile heterocyclic derivatives as adenosine receptor antagonists, compounds 20 (A 2A K i = 1.1 nM, A 1 K i = 95 nM), 21 (A 2A K i = 123 nM, A 1 K i = 25 nM), 22 (A 2A K i = 3.6 nM, A 1 K i = 18 nM), 23 (A 2A K i = 265 nM, A 1 K i = 210 nM), and 24 (A 2A K i = 7.2 nM, A 1 K i > 30000 nM) had been identified as potent A 2A antagonists. Compound 24 was an exceptionally selective A 2A antagonist with no activity for other adenosine receptors (A 1 , A 2B , and A 3 > 30 000 nM).…”

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 ].…”

Novel 8-amino-1,2,4-triazolo[4,3-a]pyrazin-3-one derivatives as potent human adenosine A1 and A2A receptor antagonists. Evaluation of their protective effect against β-amyloid-induced neurotoxicity in SH-SY5Y cells

“…In recent years, as part of a research program aimed at finding new adenosine receptor antagonists [17][18][19][20][21][22][23][24][25], we disclosed the 8-amino-1,2,4-triazolo [4,3-a]pyrazin-3-one as a new decorable scaffold to obtain potent antagonists able to bind selectively the hA 2A AR or both the hA 1 and hA 2A subtypes [21] (Fig. 1).…”