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 A(3) 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 A(3) adenosine receptor affinity in the nanomolar range and good selectivity as evaluated in radioligand binding assays at human (h) A(1), A(2A), A(2B), and A(3) 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(i)hA(1), A(2A)> 1000 nM, EC(50)hA(2B)> 1000 nM, K(i)hA(3) = 9 nM), 6d (K(i)hA(1), A(2A)> 1000 nM, EC(50)hA(2B)> 1000 nM, K(i)hA(3) = 16 nM), 6b (K(i)hA(1), A(2A)> 1000 nM, EC50-hA(2B)> 1000 nM, KihA3 = 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 A(3) receptor.