[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] Several classes of heterocyclic derivatives have been reported as AR antagonists.[2] Among them, the Schering compound, preladenant (2), a pyrazolo[4,3-e]1,2,4-triazolo[1,5-c]pyrimidine (PTP) A2A antagonist (which is under phase III clinical trials for the treatment of PD), possesses the same lateral subtituent of compound 1.[2,3] In the [1,2,4]triazolo[1,5-c]pyrimidine compound (1) the pyrazole moiety of preladenant was substituted by a phenyl spacer, leading to a compound which displays the same affinity at the A2A AR. The [1,2,4]-triazolo[1,5-c]pyrimidine 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 similar behavior of [1,2,4]triazolo[1,5-c]pyrimidines and PTPs on ARs, and our experience on PTP as A3 AR antagonists, we decided to explore the [1,2,4]triazolo[1,5-c]pyrimidine scaffold as antagonists towards A3 AR. Initially, we introduced on the bicyclic scaffold the same substituents those give affinity and selectivity at the A3 AR in the PTP nucleus. On the basis of obtained results, the optimization of substitutions allow us, after 4 series (147compounds) of [1,2,4]triazolo[1,5-c]pyrimidine derivatives, to discover a potent and selective A3 AR antagonist, with a Ki of 0.47 nM. [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.

[1,2,4]Triazolo[1,5-c]pyrimidine Nucleus as Adenosine Receptor Antagonists: Shift in Selectivity from A2A to A3 Adenosine Receptors.

FEDERICO, STEPHANIE;MORO, STEFANO;SPALLUTO, GIAMPIERO
2012

Abstract

[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] Several classes of heterocyclic derivatives have been reported as AR antagonists.[2] Among them, the Schering compound, preladenant (2), a pyrazolo[4,3-e]1,2,4-triazolo[1,5-c]pyrimidine (PTP) A2A antagonist (which is under phase III clinical trials for the treatment of PD), possesses the same lateral subtituent of compound 1.[2,3] In the [1,2,4]triazolo[1,5-c]pyrimidine compound (1) the pyrazole moiety of preladenant was substituted by a phenyl spacer, leading to a compound which displays the same affinity at the A2A AR. The [1,2,4]-triazolo[1,5-c]pyrimidine 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 similar behavior of [1,2,4]triazolo[1,5-c]pyrimidines and PTPs on ARs, and our experience on PTP as A3 AR antagonists, we decided to explore the [1,2,4]triazolo[1,5-c]pyrimidine scaffold as antagonists towards A3 AR. Initially, we introduced on the bicyclic scaffold the same substituents those give affinity and selectivity at the A3 AR in the PTP nucleus. On the basis of obtained results, the optimization of substitutions allow us, after 4 series (147compounds) of [1,2,4]triazolo[1,5-c]pyrimidine derivatives, to discover a potent and selective A3 AR antagonist, with a Ki of 0.47 nM. [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.
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Utilizza questo identificativo per citare o creare un link a questo documento: http://hdl.handle.net/11368/2834207
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