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, Ki(hA3) = 9.7 nM, IC50(hA3) = 30 nM, Ki(hA1/hA3) = 351, Ki(hA2A/hA3) > 515, IC50(hA2B) > 5 μM) 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−activity relationships and the selectivity profile of the new ligands.

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

BARALDI, Pier Giovanni;SAPONARO, Giulia;ROMAGNOLI, Romeo;AGHAZADEH TABRIZI, Mojgan;BARALDI, Stefania;GESSI, Stefania;MERIGHI, Stefania;VARANI, Katia;BOREA, Pier Andrea;PRETI, Delia
2012

Abstract

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, Ki(hA3) = 9.7 nM, IC50(hA3) = 30 nM, Ki(hA1/hA3) = 351, Ki(hA2A/hA3) > 515, IC50(hA2B) > 5 μM) 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−activity relationships and the selectivity profile of the new ligands.
2012
Baraldi, Pier Giovanni; Saponaro, Giulia; Romagnoli, Romeo; AGHAZADEH TABRIZI, Mojgan; Baraldi, Stefania; A. R., Moorman; S., Cosconati; S., Di Maro; L., Marinelli; Gessi, Stefania; Merighi, Stefania; Varani, Katia; Borea, Pier Andrea; Preti, Delia
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11392/1683521
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