RESUMO
N,N'-Disubstituted homopiperazine derivatives have been discovered as CC-chemokine receptor 2b (CCR2b) inhibitors with submicromolar activity in the CCR2b binding assay. A 4-substituted benzyl group on one homopiperazine nitrogen was an important moiety for binding affinity to the CCR2b receptor. The SAR for CCR2b binding affinity correlated inversely with the sigma factor of the functional group on this benzyl moiety. Introduction of hydroxy groups to appropriate positions in the 3,3-diphenylpropyl group on the other homopiperazine nitrogen increased CCR2b binding activity. The synthesis of an informer library to search for alternative substructures is also described.
Assuntos
Piperazinas/síntese química , Receptores de Quimiocinas/antagonistas & inibidores , Linhagem Celular , Quimiocina CCL2/metabolismo , Técnicas de Química Combinatória , Desenho de Fármacos , Humanos , Piperazinas/química , Piperazinas/farmacologia , Ensaio Radioligante , Receptores CCR2 , Relação Estrutura-AtividadeRESUMO
Structure-activity relationships (SAR) of a weakly active class of CCR2b inhibitors were utilized to initiate a lead evolution program employing the Drug Discovery Engine. Several alternative structural series have been discovered that display nanomolar activity in the CCR2b binding and CCR2b-mediated chemotaxis assays.