Novel 1,3-Dipropyl-8-(3-benzimidazol-2-yl-methoxy-1-methylpyrazol-5-yl)xanthines as Potent and Selective A2B Adenosine Receptor Antagonists

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• 作者：Pier Giovanni Baraldi ; Stefania Baraldi ; Giulia Saponaro ; Delia Preti ; Romeo Romagnoli ; Laura Piccagli ; Andrea Cavalli ; Maurizio Recanatini ; Allan R. Moorman ; Abdel Naser Zaid ; Katia Varani ; Pier Andrea Borea ; Mojgan Aghazadeh Tabrizi
• 刊名：Journal of Medicinal Chemistry
• 出版年：2012
• 出版时间：January 26, 2012
• 年：2012
• 卷：55
• 期：2
• 页码：797-811
• 全文大小：650K
• 年卷期：v.55,no.2(January 26, 2012)
• ISSN：1520-4804

文摘

Molecular modeling studies, including the comparative molecular field analysis (CoMFA) method, on 52 antagonists of the A_2B adenosine receptor with known biological activity were performed to identify the three-dimensional features responsible for A_2B adenosine receptor antagonist activity. On the basis of these and previous results on the potent antagonist effect of 8-pyrazolyl-xanthines at human A_2BAR, a new series of compounds was synthesized and evaluated in binding studies against the human A₁, A_2A, A₃, and A_2BARs. A remarkable improvement in selectivity with respect to the previous series, maintaining the potency at human A_2B receptor, was achieved, as exemplified by the 8-[3-(4-chloro-6-trifluoromethyl-1H-benzoimidazol-2-yl-methoxy)-1-methyl-1H-pyrazol-5-yl]-1,3-dipropyl-3,7-dihydro-purine-2,6-dione derivative 66: K_i A_2B = 9.4 nM, IC₅₀ hA_2B = 26 nM hA₁/hA_2B = 269, hA_2A/hA_2B > 106, hA₃/hA_2B >106. This study also led to the identification of a series of pyrazole-xanthine compounds with a simplified structure, exemplified by 8-(3-hydroxy-1-methyl-1H-pyrazol-5-yl)-xanthine 80 displaying very high affinity at A_2BAR with good selectivity over AR subtypes (K_i = 4.0 nM, IC₅₀ hA_2B = 20 nM hA₁/hA_2B = 183, hA_2A,hA₃/hA_2B > 250).