Recent developments in A2B adenosine receptor ligands

Abstract

A selective, high-affinity A2B adenosine receptor (AR) antagonist will be useful as a pharmacological tool to help determine the role of the A2BAR in inflammatory diseases and angiogenic diseases. Based on early A2BAR-selective ligands with nonoptimal pharmaceutical properties, such as 15 (MRS 1754: , and K i(hA3) = 570 nM), several groups have discovered second-generation A2BAR ligands that are suitable for development. Scientists at CV Therapeutics have discovered the selective, high-affinity A2BAR antagonist 22, a 8-(4-pyrazolyl)-xanthine derivative, (CVT-6883, ; and K i(hA 3) = 1, 070 nM). Compound 22 has demonstrated favorable pharmacokinetic (PK) properties ( and F > 35% rat), and it is a functional antagonist at the A2BAR(K B = 6 nM). In a mouse model of asthma, compound 22 demonstrated a dose-dependent efficacy supporting the role of the A2BAR in asthma. In two Phase I clinical trails, 22 (CVT-6883) was found to be safe, well tolerated, and suitable for once-daily dosing. Baraldi et al. have independently discovered a selective, high-affinity A 2BAR antagonist, 30 (MRE2029F20), 8-(5-pyrazolyl)-xanthine \,1,000)> , that has been selected for development in conjunction with King Pharmaceuticals. Compound 30 has been demonstrated to be a functional antagonist of the A2BAR, and it has been radiolabeled for use in pharmacological studies. A third compound, 58 (LAS-38096), is a 2-aminopyrimidine derivative (discovered by the Almirall group) that has high A2BAR affinity and selectivity > 1, 000 nM; K i(hA 2A) > 2, 500; and K i(hA3) > 1, 000 nM), and 58 has been moved into preclinical safety testing. A fourth selective, high-affinity A2BAR antagonist, 54 (OSIP339391 ; and was discovered by the OSI group. The three highly selective, high-affinity A2BAR antagonists that have been selected for development should prove useful in subsequent clinical trials that will establish the role of the A2BARs in various disease states. © 2009 Springer-Verlag Berlin Heidelberg.