[1,2,4]triazolo[1,5-c]pyrimidines as A(3) adenosine receptor antagonists

Question:[1,2,4]Triazolo[1,5-c]pyrimidine (TP) derivatives are reported in literature as A2A adenosine receptor (AR) antagonists useful for the treatment of Parkinson’s disease, senile dementia and depression (1).1 The Schering compound, preladenant (2), a pyrazolo[4,3-e]1,2,4-triazolo[1,5-c]pyrimidine (PTP) A2A antagonist, possesses a lateral substituent similar to those of the TP compound 1.2,3 Although these two compounds are both potent A2A antagonist, the TP nucleus possesses a simpler structure and less nitrogen atoms than PTPs, thus it may be a scaffold with promising pharmacokinetics properties. So, starting from the structural similarity between TP and PTP A2A AR antagonists, and our experience on PTP nucleus as A3 AR antagonists, we decided to explore the TP scaffold in order to obtain potent antagonists towards A3 AR. Methods: All compounds were synthesized according to literature1 and have been evaluated for potency at all four human ARs. Results: Initially, we introduced at the 5 position of the TP scaffold the same substituents which gave affinity and selectivity at the A3 AR at the 5 position in the PTP nucleus. On the basis of obtained results, the optimization of substitutions at the 5, 8 and 2 positions, which led to 147 [1,2,4]triazolo[1,5-c]pyrimidine derivatives, allowed us to reach subnanomolar Ki values at the A3 AR and good levels of selectivity versus the other adenosine receptor subtypes. Conclusions: A novel promising class of potent and selective A3 adenosine receptor antagonist with a [1,2,4]triazolo[1,5-c]pyrimidine nucleus was discovered. References: [1] Kyowa Hakko Kogyo Cp., Ltd., Tokyo (JP). Shimada, J.; Imma, H.; Osakada, N.; Shiozaki, S.; Kanda, T.; Kuwana, Y. [1,2,4]Triazolo[1,5-c]pyrimidine derivatives. 2003, US6545000. [2] Muller, C.E.; Jacobson, K.A. Recent developments in adenosine receptor ligands and their potential as novel drugs. Biochim. Biophys. Acta. 2011, 1808, 1290–1308. [3] Neustadt, B.R.; Hao, J., Lindo, N.; Greenlee, W.J.; Stamford, A.W.; Tulshian, D.; Ongini, E.; Hunter, J.; Monopoli, A.; Bertorelli, R.; Foster, C.; Arik, L.; Lachowicz, J.; Nga, K.; Feng, K.I. Potent, selective, and orally active adenosine A2A receptor antagonists: arylpiperazine derivatives of pyrazolo[4,3-e][1,2,4]triazolo[1,5-c]pyrimidines. Bioorg. Med. Chem. Lett. 2007, 17, 1376–1380.