Recent Developments in A_2B Adenosine Receptor Ligands

Abstract

A selective, high-affinity A_2B adenosine receptor (AR) antagonist will be useful as a pharmacological tool to help determine the role of the A_2BAR in inflammatory diseases and angiogenic diseases. Based on early A_2BAR-selective ligands with nonoptimal pharmaceutical properties, such as 15 (MRS 1754: ${K}_{\mathrm{i}}(\mathrm{h{A}_{2B}})\;=\;2\,\mathrm{nM};\ {K}_{\mathrm{i}}({\mathrm{hA}}_{1})\;=\;403\,\mathrm{nM};\ {K}_{\mathrm{i}}(\mathrm{h{A}_{2A}})\;=\;503\,\mathrm{nM}$, and K _i(hA₃) = 570 nM), several groups have discovered second-generation A_2BAR ligands that are suitable for development. Scientists at CV Therapeutics have discovered the selective, high-affinity A_2BAR antagonist 22, a 8-(4-pyrazolyl)-xanthine derivative, (CVT-6883, ${K}_{\mathrm{i}}(\mathrm{h{A}_{2B}}) = 22\,\mathrm{nM};\ {K}_{\mathrm{i}}({\mathrm{hA}}_{1}) = 1,940\,\mathrm{nM};\ {K}_{\mathrm{i}}(\mathrm{h{A}_{2A}})\,=\,3,280$; and K _i(hA₃) = 1, 070 nM). Compound 22 has demonstrated favorable pharmacokinetic (PK) properties (${T}_{1/2}\,=\,4\,\mathrm{h}$ and F > 35% rat), and it is a functional antagonist at the A_2BAR(K _B = 6 nM). In a mouse model of asthma, compound 22 demonstrated a dose-dependent efficacy supporting the role of the A_2BAR 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 $({K}_{\mathrm{i}}(\mathrm{h{A}_{2B}}) = 5.5\,\mathrm{nM};{K}_{\mathrm{i}}({\mathrm{hA}}_{1}) = 200\,\mathrm{nM};{K}_{\mathrm{i}}(\mathrm{h{A}_{2A},\ {A}_{3}})\,>\,1,000)$, that has been selected for development in conjunction with King Pharmaceuticals. Compound 30 has been demonstrated to be a functional antagonist of the A_2BAR, 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 A_2BAR affinity and selectivity $({K}_{\mathrm{i}}(\mathrm{h{A}_{2B}})\,=\,17\,\mathrm{nM};\ {K}_{\mathrm{i}}({\mathrm{hA}}_{1})\,>$ 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 A_2BAR antagonist, 54 (OSIP339391 ${K}_{\mathrm{i}}(\mathrm{h{A}_{2B}})\,=\,0.5\,\mathrm{nM};\ {K}_{\mathrm{i}}({\mathrm{hA}}_{1})\,=\,37\,\mathrm{nM};\ {K}_{\mathrm{i}}(\mathrm{h{A}_{2A}})\,=\,328$; and ${K}_{\mathrm{i}}({\mathrm{hA}}_{3})\,=\,450\,\mathrm{nM})$ was discovered by the OSI group. The three highly selective, high-affinity A_2BAR antagonists that have been selected for development should prove useful in subsequent clinical trials that will establish the role of the A_2BARs in various disease states.