RESUMO
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).
Assuntos
Antagonistas do Receptor A2 de Adenosina/química , Quinolonas/química , Receptor A2B de Adenosina/química , Antagonistas do Receptor A2 de Adenosina/síntese química , Antagonistas do Receptor A2 de Adenosina/farmacologia , Técnicas de Química Combinatória , Avaliação Pré-Clínica de Medicamentos , Humanos , Microssomos Hepáticos/metabolismo , Quinolonas/síntese química , Quinolonas/farmacologia , Receptor A2B de Adenosina/metabolismo , Relação Estrutura-AtividadeRESUMO
-4-Amino-2-arylbutylbenzamides such as 1 were identified as micromolar MCH 1 receptor (MCH1R) antagonists via screening using a scintillation proximity assay based on [125I]-MCH binding to recombinant, human MCH1R. Subsequent lead optimization efforts using solid-phase parallel synthesis resulted in the defined structure-activity relationships and the identification of 4-amino-2-biarylbutylureas, such as 11g, as potent single digit nanomolar MCH1R antagonists.