New 2-arylpyrazolo[4,3-c]quinoline derivatives as potent and selective human A(3) 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) A1, 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 ihA 1, A 2A> 1000 nM, EC 50hA 2B> 1000 nM, K ihA 3 = 9 nM), 6d (K ihA 1, A 2A> 1000 nM, EC 50hA 2B> 1000 nM, K ihA 3 = 16 nM), 6b (K ihA 1, A 2A > 1000 nM, EC 50-hA 2B> 1000 nM, K ihA 3 = 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. © 2005 American Chemical Society.