The selective, high affinity A_2B adenosine receptor (AdoR) antagonists that were synthesized by several research groups should aid in determining the role of the A_2B AdoR in inflammatory diseases like asthma or rheumatoid arthritis (RA) and angiogenic diseases like diabetic retinopathy or cancer. CV Therapeutics scientists discovered the selective, high affinity A_2B AdoR antagonist 10, a 8-(4-pyrazolyl)-xanthine derivative [CVT-6883, K_i(hA_2B) = 22 nM; K_i(hA₁) = 1,940 nM; K_i(hA_2A) = 3,280; and K_i(hA₃) = 1,070 nM] that has favorable pharmacokinetic (PK) properties (t _1/2 = 4 h and F > 35% rat). Compound 10 demonstrated functional antagonism at the A_2B AdoR (K_B = 6 nM) and efficacy in a mouse model of asthma. In two phase 1 clinical trials, CVT-6883 was found to be safe, well tolerated, and suitable for once daily dosing. A second compound 20, 8-(5-pyrazolyl)-xanthine, has been nominated for development from Baraldi’s group in conjunction with King Pharmaceuticals that has favorable A_2B AdoR affinity and selectivity [K_i(hA_2B) = 5.5 nM; K_i(hA₁) > 1,000 nM; K_i(hA_2A) > 1,000; and K_i(hA₃) > 1,000 nM], and it has been demonstrated to be a functional antagonist. A third compound 32, a 2-aminopyrimidine, from the Almirall group has high A_2B AdoR affinity and selectivity [K_i(hA_2B) = 17 nM; K_i(hA₁) > 1,000 nM; K_i(hA_2A) > 2,500; and K_i(hA₃) > 1,000 nM], and 32 has been moved into preclinical safety testing. Since three highly selective, high affinity A_2B AdoR antagonists have been nominated for development with 10 (CVT-6883) being the furthest along in the development process, the role of the A_2B AdoR in various disease states will soon be established.