Derivatives of 4-Amino-6-hydroxy-2-mercaptopyrimidine as Novel, Potent, and Selective A3 Adenosine Receptor Antagonists

详细信息    查看全文

• 作者：Barbara Cosimelli ; Giovanni Greco ; Marina Ehlardo ; Ettore Novellino ; Federico Da Settimo ; Sabrina Taliani ; Concettina La Motta ; Marusca Bellandi ; Tiziano Tuccinardi ; Adriano Martinelli ; Osele Ciampi
• 刊名：Journal of Medicinal Chemistry
• 出版年：2008
• 出版时间：March 27, 2008
• 年：2008
• 卷：51
• 期：6
• 页码：1764 - 1770
• 全文大小：393K
• 年卷期：v.51,no.6(March 27, 2008)
• ISSN：1520-4804

文摘

A number of derivatives of 4-amino-6-hydroxy-2-mercaptopyrimidine (5) were synthesized and biologically evaluated as A₃ adenosine receptor (A₃ AR) antagonists. The new compounds were designed as open chain analogues of a triazolopyrimidinone derivative displaying submicromolar affinity for the A₃ AR, which had been previously identified using a 3D database search. Substituents R, R′, and R′′ attached to the parent compound 5 were chosen according to factorial design and stepwise lead optimization approaches, taking into account the essentially hydrophobic nature of the A₃ AR binding site. As a result, 5m (R = n-C₃H₇, R′ = 4-ClC₆H₄CH₂, R′′ = CH₃) was identified among the pyrimidine derivatives as the ligand featuring the best combination of potency and selectivity for the target receptor. This compound binds to the A₃ AR with a K_i of 3.5 nM and is devoid of appreciable affinity for the A₁, A_2A, and A_2B ARs.