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.
Asunto(s)
Aminoácidos/química , Aminoácidos/farmacología , Bencilaminas/química , Bencilaminas/farmacología , Receptores CXCR3/antagonistas & inhibidores , Aminoácidos/farmacocinética , Animales , Bencilaminas/farmacocinética , Células CACO-2 , Descubrimiento de Drogas , Humanos , Ratones , Microsomas Hepáticos/metabolismo , Receptores CXCR3/metabolismoRESUMEN
The effect of the isoquinoline derivative, drotaverine on the specific binding of [(3)H]nitrendipine and [(3)H]diltiazem to pregnant rat uterine membranes was examined. Drotaverine inhibited the specific [(3)H]nitrendipine and [(3)H]diltiazem bindings with IC(50) values of 5.6 and 2.6 microM, respectively. Saturation studies showed that diltiazem caused a significant increase in the maximum binding density without changing the K(D) of [(3)H]nitrendipine while drotaverine increased both the K(D) and the B(max) of [3H]nitrendipine. The dissociation kinetics of both [3H]nitrendipine and [(3)H]diltiazem were accelerated by drotaverine. These results suggest that drotaverine has a negative allosteric interaction with the binding sites for 1,4-dihydropyridines and 1,5-benzothiazepines on the L-type Ca(2+) channel in pregnant rat uterine membranes, which may have implications as to the potential usefulness of this drug in aiding child delivery.
