The Identification of the 2-Phenylphthalazin-1(2H)-one Scaffold as a New Decorable Core Skeleton for the Design of Potent and Selective Human A3 Adenosine Receptor Antagonists

详细信息    查看全文

• 作者：Daniela Poli ; Daniela Catarzi ; Vittoria Colotta ; Flavia Varano ; Guido Filacchioni ; Simona Daniele ; Letizia Trincavelli ; Claudia Martini ; Silvia Paoletta ; Stefano Moro
• 刊名：Journal of Medicinal Chemistry
• 出版年：2011
• 出版时间：April 14, 2011
• 年：2011
• 卷：54
• 期：7
• 页码：2102-2113
• 全文大小：1098K
• 年卷期：v.54,no.7(April 14, 2011)
• ISSN：1520-4804

文摘

Following a molecular simplification approach, we have identified the 2-phenylphthalazin-1(2H)-one (PHTZ) ring system as a new decorable core skeleton for the design of novel hA₃ adenosine receptor (AR) antagonists. Interest for this new series was driven by the structural similarity between the PHTZ skeleton and both the 2-aryl-1,2,4-triazolo[4,3-a]quinoxalin-1-one (TQX) and the 4-carboxamido-quinazoline (QZ) scaffolds extensively investigated in our previously reported studies. Our attention was focused at position 4 of the phthalazine nucleus where different amido and ureido moieties were introduced (compounds 2鈭?b>20). Some of the new PHTZ compounds showed high hA₃ AR affinity and selectivity, the 2,5-dimethoxyphenylphthalazin-1(2H)-one 18 being the most potent and selective hA₃ AR antagonist among this series (K_i = 0.776 nM; hA₁/hA₃ and hA_2A/hA₃ > 12000). Molecular docking studies on the PHTZ derivatives revealed for these compounds a binding mode similar to that of the previously reported TQX and QZ series, as was expected from the simplification approach.