期刊
JOURNAL OF MEDICINAL CHEMISTRY
卷 52, 期 23, 页码 7640-7652出版社
AMER CHEMICAL SOC
DOI: 10.1021/jm900718w
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资金
- Italian Ministry for University and Research (MIUR) [FIRB RBNE03YA3L]
A molecular simplification approach of previously reported 2-arylpyrazolo[3,4-c]quinolin-4-ones was applied to design 2-arylpyrazolo[4,3-d]pyrimidin-7-one derivatives as new human A(3) adenosine receptor antagonists. Substituents with different lipophilicity and steric hindrance were introduced at the 5-position of the bicyclic Scaffold (R-5 = H, Me, Et, Ph, CH2Ph) and on the 2-phenyl ring (OMe, Me). Most of the synthesized derivatives were highly potent hA(3) adenosine receptor antagonists, the best being the 2-(4-methoxyphenyl)pyrazolo[4,3-d]pyrimidin-7-one (K-i = 1.2 nM). The new compounds were also highly selective, being completely devoid of affinity toward hA(1), hA(2A), and hA(2B) adenosine receptors. On the basis of the recently published human A(2A) receptor crystallographic information, we propose it novel receptor-driven hypothesis to explain both A(3) AR affinity and A(3) versus A(2A) Selectivity profiles of these new antagonists.
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