title: Recent developments in A2B 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(2B)AR in inflammatory diseases and angiogenic diseases. Based on early A(2B)AR-selective ligands with nonoptimal pharmaceutical properties, such as 15 (MRS 1754: K(i)(hA(2B)) = 2 nM; K(i)(hA(1)) = 403 nM; K(i)(hA(2A)) = 503 NM, and K(i)(hA(3)) = 570 nM), several groups have discovered second-generation A(2B)AR ligands that are suitable for development. Scientists at CV Therapeutics have discovered the selective, high-affinity A(2B)AR antagonist 22, a 8-(4-pyrazolyl)-xanthine derivative, (CVT-6883, K(i)(hA(2B)) = 22 nM; K(i)(hA(1)) = 1,940 nM; K(i)(hA(2A)) = 3,280; and K(i)(hA(3)) = 1,070 nM). Compound 22 has demonstrated favorable pharmacokinetic (PK) properties (T(1/2) = 4 h and F > 35% rat), and it is a functional antagonist at the A(2B)AR(K (B) = 6 nM). In a mouse model of asthma, compound 22 demonstrated a dose-dependent efficacy supporting the role of the A(2B)AR 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(2B)AR antagonist, 30 (MRE2029F20), 8-(5-pyrazolyl)-xanthine (K(i)(hA(2B)) = 5.5 nM; K(i)(hA(1)) = 200 nM; K(i)(hA(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(2B)AR, 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(2B)AR affinity and selectivity (K(i)(hA(2B)) = 17 nM; K(i)(hA(1)) > 1,000 nM; K(i)(hA(2A)) > 2,500; and K(i)(hA(3)) > 1,000 nM), and 58 has been moved into preclinical safety testing. A fourth selective, high-affinity A(2B)AR antagonist, 54 (OSIP339391 K(i))(hA(2B)) = 0.5 nM; K(i))(hA(1)) = 37 nM; K(i))(hA(2A)) = 328; and K(i))(hA(3)) = 450 nm) was discovered by the OSI group. The three highly selective, high-affinity A(2B)AR antagonists that have been selected for development should prove useful in subsequent clinical trials that will establish the role of the A(2B)ARs in various disease states.
authors.affiliation: Department of Medicinal Chemistry, CV Therapeutics Inc., Palo Alto, CA 94304, USA. rao.kalla@cvt.com
authors.forename: Rao V
authors.initials: RV
authors.lastname: Kalla
authors.forename: Jeff
authors.initials: J
authors.lastname: Zablocki
authors.forename: Mojgan Aghazadeh
authors.initials: MA
authors.lastname: Tabrizi
authors.forename: Pier Giovanni
authors.initials: PG
authors.lastname: Baraldi
mesh_terms: D000225:Adenine / Q000494:pharmacology; D058917:Adenosine A2 Receptor Antagonists; D000631:Aminopyridines / Q000494:pharmacology; D000818:Animals; D001249:Asthma / Q000209:etiology; D055808:Drug Discovery; D006801:Humans; D011719:Pyrazines / Q000494:pharmacology; D011743:Pyrimidines / Q000494:pharmacology; D043704:Receptor, Adenosine A2B / Q000502:physiology; D014970:Xanthines / Q000494:pharmacology
chemical_list: D058917:Adenosine A2 Receptor Antagonists; D000631:Aminopyridines; D011719:Pyrazines; D011743:Pyrimidines; D043704:Receptor, Adenosine A2B; D014970:Xanthines; D000225:Adenine