Selective, high affinity A2B adenosine receptor antagonists: N-1 monosubstituted 8-(pyrazol-4-yl)xanthines

A series of N-1 monosubstituted 8-pyrazolyl xanthines have been synthesized and evaluated for their affinity for the adenosine receptors (AdoRs). We have discovered two compounds 18 (CVT-7124) and 28 (CVT-6694) that display good affinity for the A2B AdoR (Ki = 6 nM and 7 nM, respectively) and greater selectivity for the human A1, A2A, and A3 AdoRs (>1000-, >830-, and >1500-fold; >850-, >700-, and >1280-fold, respectively). CVT-6694 has been shown to block the release of interleukin-6 and monocyte chemotactic protein-1 from bronchial smooth muscle cells (BSMC), a process believed to be promoted by activation of A2B AdoR.

We describe the synthesis of a series of N-1 monosubstituted 8-pyrazolyl xanthines, as high affinity and selective adenosine A2B receptor antagonists. [CVT-6694; A2B AdoR Ki = 7 nM, selectivity A1 > 850: A2A > 700: A3 > 1280].Figure optionsDownload as PowerPoint slide