RESUMEN
Starting with our previously described(20) class of CC chemokine receptor-3 (CCR3) antagonist, we improved the potency by replacing the phenyl linker of 1 with a cyclohexyl linker and by replacing the 4-benzylpiperidine with a 3-benzylpiperidine. The resulting compound, 32, is a potent and selective antagonist of CCR3. SAR studies showed that the 3-acetylphenyl urea of 32 could be replaced with heterocyclic ureas or heterocyclic-substituted phenyl ureas and still maintain the potency (inhibition of eotaxin-induced chemotaxis) of this class of compounds in the low-picomolar range (IC(50) = 10-60 pM), representing some of the most potent CCR3 antagonists reported to date. The potency of 32 for mouse CCR3 (chemotaxis IC(50) = 41 nM) and its oral bioavailability in mice (20% F ) were adequate to assess the efficacy in animal models of allergic airway inflammation. Oral administration of 32 reduced eosinophil recruitment into the lungs in a dose-dependent manner in these animal models. On the basis of its overall potency, selectivity, efficacy, and safety profile, the benzenesulfonate salt of 32, designated DPC168, entered phase I clinical trials.
Asunto(s)
Ciclohexanos/síntesis química , Compuestos de Fenilurea/síntesis química , Piperidinas/síntesis química , Receptores de Quimiocina/antagonistas & inhibidores , Animales , Disponibilidad Biológica , Células CHO , Células CACO-2 , Calcio/metabolismo , Quimiotaxis de Leucocito/efectos de los fármacos , Cricetinae , Ciclohexanos/química , Ciclohexanos/farmacología , Eosinófilos/efectos de los fármacos , Eosinófilos/fisiología , Femenino , Humanos , Hipersensibilidad/tratamiento farmacológico , Hipersensibilidad/inmunología , Técnicas In Vitro , Inflamación/tratamiento farmacológico , Masculino , Ratones , Ratones Endogámicos BALB C , Ratones Endogámicos C57BL , Permeabilidad , Compuestos de Fenilurea/química , Compuestos de Fenilurea/farmacología , Piperidinas/química , Piperidinas/farmacología , Receptores CCR3 , Estereoisomerismo , Relación Estructura-Actividad , Urea/análogos & derivados , Urea/síntesis química , Urea/química , Urea/farmacologíaRESUMEN
Structure-activity relationship (SAR) studies of initial screening hits from our corporate library of compounds and a structurally related series of CCR1 receptor antagonists were used to determine that an N-(alkyl)benzylpiperidine is an essential pharmacophore for selective CCR3 antagonists. Further SAR studies that introduced N-(ureidoalkyl) substituents improved the binding potency of these compounds from the micromolar to the low nanomolar range. This new series of compounds also displays highly potent, in vitro functional CCR3-mediated antagonism of eotaxin-induced Ca(2+) mobilization and chemotaxis of human eosinophils.
