1,2,4]Triazolo[1,5-c]pyrimidines as New Potent Human A3 Adenosine Receptor Antagonists.

[1,2,4]Triazolo[1,5-c]pyrimidine derivatives are reported in literature as A2A adenosine receptor (AR) antagonists useful for the treatment of Parkinson’s disease (PD), senile dementia and depression (1).1 We decided to explore the [1,2,4]triazolo[1,5-c]pyrimidine scaffold in order to obtain antagonists selective towards hA3 AR. Inactivation of the A3 AR is being studied in glaucoma but also in inflammatory diseases such as asthma.2 In a previous work, we have found that, in order to obtain good hA3 AR antagonists, the better substitutions at the 5 and 8 positions are a little alkylamino (methyl or ethylamino) and an ethylester moieties, respectively. Here we report a novel series of [1,2,4]triazolo[1,5-c]pyrimidines where we have introduced different alkyl, cycloalkyl, aryl and heteroaryl moieties at the 2 position (2). Surprisingly, the introduction of substituted-phenyl rings led to subnanomolar affinities at the hA3 AR. The best compound of this series is represented by the ethyl 2-(4-methoxyphenyl)-5-(methylamino)-[1,2,4]triazolo[1,5-c]pyrimidine-8-carboxylate (3) which shows a Ki of 0.47 nM towards hA3 AR and a 4200- and 8400-fold selectivity over hA1 and hA2A ARs, respectively.1. Shimada, J.; Imma, H.; Osakada, N.; Shiozaki, S.; Kanda, T.; Kuwana, Y. [1,2,4]Triazolo[1,5-c]pyrimidine derivatives. 2003, US6545000. 2. Cheong, S.L; Federico, S.; Venkatesan, G.; Mandel, A.L.; Shao, Y.M.; Moro, S.; Spalluto, G.; Pastorin, G. The A3 adenosine receptor as multifaceted therapeutic target: pharmacology, medicinal chemistry and in silico approaches. Med. Res. Rev. 2013, 33, 235-335.