RESUMEN
A novel series of adenosine A(2A) receptor antagonists was identified by high-throughput screening of an encoded combinatorial compound collection. The initial hits were optimized for A(2A) binding affinity, A(1) selectivity, and in vitro microsomal stability generating orally available 2-aminoimidazo[4,5-b]pyridine-based A(2A) antagonist leads.
Asunto(s)
Pirimidinas/farmacología , Receptor de Adenosina A2A/efectos de los fármacos , Descubrimiento de Drogas , Humanos , Enlace de Hidrógeno , Microsomas/efectos de los fármacos , Receptor de Adenosina A2A/químicaRESUMEN
A novel series of quinolinone-based adenosine A(2B) receptor antagonists was identified via high throughput screening of an encoded combinatorial compound collection. Synthesis and assay of a series of analogs highlighted essential structural features of the initial hit. Optimization resulted in an A(2B) antagonist (2i) which exhibited potent activity in a cAMP accumulation assay (5.1 nM) and an IL-8 release assay (0.4 nM).