RESUMEN
N,N-Disubstituted benzylamine derivatives have been identified as CXCR3 antagonists. Compounds were optimized to improve affinity and selectivity, to increase metabolic stability in human and mouse liver microsomes, to increase Caco-2 permeability. Optimization was supported by monitoring physico-chemical properties using both experimental and computational means. Several compounds with double-digit nanomolar CXCR3 affinity, favorable selectivity, microsomal stability, Caco-2 permeability and human hepatocyte clearance have been identified.
Asunto(s)
Bencilaminas/química , Bencilaminas/farmacología , Receptores CXCR3/antagonistas & inhibidores , Receptores CXCR3/metabolismo , Animales , Bencilaminas/farmacocinética , Células CACO-2 , Humanos , Ratones , Microsomas Hepáticos/metabolismo , Modelos Moleculares , Relación Estructura-ActividadRESUMEN
A new series of beta amino acids, which act as CXCR3 antagonists, has been identified. The formerly optimized N,N-disubstituted benzylamine derivatives with carboxylic acid function on the N-atom was used as starting point and compounds with carboxyl function not attached to the N-atom were investigated. Affinity, metabolic stability in human and mouse liver microsomes and Caco-2 permeability were optimized. Compounds with double-digit nanomolar CXCR3 affinity, favourable microsomal stability and Caco-2 permeability have been identified.
