RESUMEN
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).
Asunto(s)
Antagonistas del Receptor de Adenosina A2/química , Quinolonas/química , Receptor de Adenosina A2B/química , Antagonistas del Receptor de Adenosina A2/síntesis química , Antagonistas del Receptor de Adenosina A2/farmacología , Técnicas Químicas Combinatorias , Evaluación Preclínica de Medicamentos , Humanos , Microsomas Hepáticos/metabolismo , Quinolonas/síntesis química , Quinolonas/farmacología , Receptor de Adenosina A2B/metabolismo , Relación Estructura-ActividadRESUMEN
Aryl iodides (ArI) couple with aryl aldehydes (Ar'CHO) in the presence of Ni(dppe)Br(2) and Zn to give the corresponding biaryl ketones (ArCOAr'). The use of a bidentate phosphine complex is critical to the success of this catalytic reaction. The reaction provides a new procedure for the synthesis of various functionalized biaryl ketones.