New 2-Arylpyrazolo[4,3-c]quinoline Derivatives as Potent and Selective Human A₃ Adenosine Receptor Antagonists

In this paper we report the synthesis and biological evaluation of a new class of 2-phenyl-2,5-dihydro-pyrazolo[4,3-c]quinolin-4-ones as A₃ adenosine receptor antagonists. We designed a new route based on the Kira-Vilsmeier reaction for the synthesis of this class of compounds. Some of the synthesized compounds showed A₃ adenosine receptor affinity in the nanomolar range and good selectivity as evaluated in radioligand binding assays at human (h) A₁, A_2A, A_2B, and A₃ adenosine receptor subtypes. We introduced several substituents on the 2-phenyl ring. In particular substitution at the 4-position by methyl, methoxy, and chlorine gave optimal activity and selectivity 6c (K_ihA₁, A_2A>1000 nM, EC₅₀hA_2B>1000 nM, K_ihA₃ = 9 nM), 6d (K_ihA₁, A_2A>1000 nM, EC₅₀hA_2B>1000 nM, K_ihA₃ = 16 nM), 6b (K_ihA₁, A_2A >1000 nM, EC₅₀hA_2B>1000 nM, K_ihA₃ = 19 nM). In conclusion, the 2-phenyl-2,5-dihydro-pyrazolo[4,3-c]quinolin-4-one derivatives described herein represent a new family of in vitro selective antagonists for the adenosine A₃ receptor.