Pyrido[2,1-f]purine-2,4-dione derivatives as a novel class of highly potent human A3 adenosine receptor antagonists

Article abstract of DOI:10.1021/jm0208469

1H,3H-Pyrido[2,1-f]purine-2,4-diones, which can be described as fused xanthine structures, have been synthesized by a novel synthetic procedure, and their affinities for the human adenosine A₁, A_2A, and A₃ receptors have been evaluated in radioligand binding studies. The synthetic procedure employed was developed in our laboratory and involved a two-step one-pot reaction that consists of the treatment of 6-aminouracil derivatives with N-bromosuccinimide to generate a 5,5-dibromo-6-imino intermediate that reacts "in situ" with pyridine, 4-methoxypyridine, 4-tert-butylpyridine, or 4-phenylpyridine to afford the corresponding 1H,3H-pyrido-[2,1-f]purine-2,4-diones (2-5). Functionalization at the N³ position in compounds 2-5 was performed by reaction with DBU and different alkyl, alkenyl, alkynyl, or benzyl halides. Binding studies at human adenosine A₁, A_2A, and A₃ receptors revealed significant antagonist effects in the low nanomolar range, in particular against the A₃ receptor. Thus, the 1-benzyl-3-propyl-1H,3H-pyrido[2,1-f]purine-2,4-dione derivative 6, which can be considered a lead compound in this series, exhibited a K_i value of 4.0 ± 0.3 nM against the h_A3 receptor. Because xanthine derivatives have traditionally been considered poor A₃ antagonists, the described pyrido[2,1-f]purine-2,4-dione derivatives represent a new family of adenosine receptor antagonists which deserves further exploration.