Water-Soluble Pyrazolo[4,3-e][1,2,4]triazolo[1,5-c]pyrimidines as Human A3 Adenosine Receptor Antagonists

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• 作者：Pier Giovanni Baraldi ; Giulia Saponaro ; Romeo Romagnoli ; Mojgan Aghazadeh Tabrizi ; Stefania Baraldi ; Allan R. Moorman ; Sandro Cosconati ; Salvatore Di Maro ; Luciana Marinelli ; Stefania Gessi ; Stefania Merighi ; Katia Varani ; Pier Andrea Borea ; Delia Preti
• 刊名：Journal of Medicinal Chemistry
• 出版年：2012
• 出版时间：June 14, 2012
• 年：2012
• 卷：55
• 期：11
• 页码：5380-5390
• 全文大小：461K
• 年卷期：v.55,no.11(June 14, 2012)
• ISSN：1520-4804

文摘

A relevant problem of the pyrazolo[4,3-e][1,2,4]triazolo[1,5-c]pyrimidine nucleus, an attractive scaffold for the preparation of adenosine receptor antagonists, is the low water solubility. We originally functionalized the C⁵ position with a salifiable 4-pyridylcarbamoyl moiety that conferred good water solubility at low pH (<4.0) but poor solubility at physiologic pH, indicative of the dissociation of the pyridinium species. Here we replaced the pyridin-4-yl moiety with a 1-(substituted)piperidin-4-yl ring to exploit the higher basicity of this nucleus and for the the possibility to generate stable, water-soluble salts. The hydrochloride salt of the 1-(cyclohexylmethyl)piperidin-4-yl derivative (10, K_i(hA₃) = 9.7 nM, IC₅₀(hA₃) = 30 nM, K_i(hA₁/hA₃) = 351, K_i(hA_2A/hA₃) > 515, IC₅₀(hA_2B) > 5 渭M) showed a solubility of 8 mg/mL at physiological pH and gave a stable aqueous system suitable for intravenous infusion. Molecular modeling studies were helpful in rationalizing the available structure鈥揳ctivity relationships and the selectivity profile of the new ligands.