Discovery Of Las101057: A Potent, Selective, And Orally Efficacious A(2b) Adenosine Receptor Antagonist

The structure activity relationships for a series of pyrazine-based A(2B) adenosine receptor antagonists are described. From this work, LAS101057 (17), a potent, selective, and orally efficacious A(2B) receptor antagonist, was identified as a clinical development candidate. LAS101057 inhibits agonist-induced IL-6 production in human fibroblasts and is active in an ovalbumin (OVA)-sensitized mouse model after oral administration, reducing airway hyperresponsiveness to methacholine, Th2 cytokine production, and OVA-specific IgE levels.