RESUMEN
Activation of CCR8 by its ligand CCL1 may play an important role in diseases such as asthma, multiple sclerosis, and cancer. The study of small molecule CCR8 antagonists will help establish the validation of these hypotheses. We report the design, synthesis, and progress toward optimization of potent small molecule CCR8 antagonists identified from a high-throughput screen. These analogues exhibit good potency in binding and chemotaxis assays, show good selectivity versus the hERG channel, and have good eADME (early absorption, distribution, metabolism, and excretion) profiles.
Asunto(s)
Diseño de Fármacos , Receptores de Quimiocina/antagonistas & inhibidores , Aminación , Línea Celular , Quimiotaxis/efectos de los fármacos , Éter/química , Humanos , Estructura Molecular , Piperidinas/síntesis química , Piperidinas/química , Piperidinas/farmacología , Pirrolidinas/síntesis química , Pirrolidinas/química , Pirrolidinas/farmacología , Receptores CCR8 , Relación Estructura-ActividadRESUMEN
Drug-induced QT prolongation arising from drugs' blocking of hERG channel activity presents significant challenges in drug development. Many, but not all, of our benzamidine-containing factor Xa inhibitors were found to have high hERG binding propensity. However, incorporation of a carboxylic acid group into these benzamidine molecules generally leads to hERG inactive compounds regardless where the carboxyl group is tethered within the molecules. The inhibitory effect of a carboxylic acid group on hERG binding has also been observed in many series of diverse structural scaffolds (including non-amidines). These findings suggest that the negatively charged carboxylate group causes unfavorable interaction within hERG channel binding cavity by electrostatic interaction.