RESUMEN
A series of compounds which exhibited good human CCR1 binding and functional potency was modified resulting in the discovery of a novel series of high affinity, functionally potent antagonists of the CCR1 receptor. Issues of PXR activity, ion-channel potency, and poor metabolic stability were addressed by the addition of a hydroxyl group to an otherwise lipophilic area in the molecule resulting in the discovery of preclinical candidate BMS-457 for the treatment of rheumatoid arthritis.
Asunto(s)
Descubrimiento de Drogas , Piperidinas/farmacología , Receptores CCR1/antagonistas & inhibidores , Relación Dosis-Respuesta a Droga , Humanos , Estructura Molecular , Piperidinas/síntesis química , Piperidinas/química , Relación Estructura-ActividadRESUMEN
High-affinity, functionally potent, urea-based antagonists of CCR1 have been discovered. Modulation of PXR transactivation has revealed the selective and orally bioavailable CCR1 antagonist BMS-817399 (29), which entered clinical trials for the treatment of rheumatoid arthritis.