RESUMEN
SAR studies were conducted around lead compound 1 using high-throughput parallel solution and solid phase synthesis. Our lead optimization efforts led to the identification of several CCR2b antagonists with potent activity in both binding and functional assays [Compound 71 CCR2b Binding IC(50) 3.2 nM; MCP-1-Induced Chemotaxis IC(50) 0.83 nM; Ca(2+) Flux IC(50) 7.5 nM].
Asunto(s)
Quimiocina CCL2/metabolismo , Quimiotaxis/efectos de los fármacos , Pirrolidinas/farmacología , Receptores CCR2/antagonistas & inhibidores , Calcio/metabolismo , Células Cultivadas , Cromatografía Líquida de Alta Presión , Fluorescencia , Humanos , Riñón/citología , Riñón/efectos de los fármacos , Riñón/metabolismo , Estructura Molecular , Monocitos/efectos de los fármacos , Monocitos/metabolismo , Pirrolidinas/síntesis química , Receptores CCR2/metabolismo , Relación Estructura-Actividad , TransfecciónRESUMEN
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.
Asunto(s)
Piperazinas/síntesis química , Receptores de Quimiocina/antagonistas & inhibidores , Línea Celular , Quimiocina CCL2/metabolismo , Técnicas Químicas Combinatorias , Diseño de Fármacos , Humanos , Piperazinas/química , Piperazinas/farmacología , Ensayo de Unión Radioligante , Receptores CCR2 , Relación Estructura-ActividadRESUMEN
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.