RESUMEN
The identification, optimization, and structure-activity relationship (SAR) of small-molecule CCR4 antagonists is described. An initial screening hit with micromolar potency was identified that was optimized to sub-micromolar binding potency by enantiomer resolution, halogenation of the naphthalene ring, and extension of the alkyl chain linker between the central piperidine ring and the terminal aryl group. An antagonist was identified that showed good cross-reactivity against the mouse receptor and inhibited CCR4-based cell recruitment in dose-dependent fashion.
Asunto(s)
Antiinflamatorios no Esteroideos/química , Antiinflamatorios no Esteroideos/farmacología , Naftalenos/química , Naftalenos/farmacología , Receptores de Quimiocina/antagonistas & inhibidores , Sulfonamidas/química , Sulfonamidas/farmacología , Animales , Antiinflamatorios no Esteroideos/síntesis química , Ratones , Ratones Endogámicos BALB C , Naftalenos/síntesis química , Receptores CCR4 , Relación Estructura-Actividad , Sulfonamidas/síntesis químicaRESUMEN
Starting with a micromolar lead identified from high-throughput screening, a series of pyrazoles were discovered with significantly improved potency on bacterial methionyl-tRNA synthetase and selectivity over human methionyl-tRNA synthetase.